P-459: A Randomized, Controlled Phase 2 Trial of Uproleselan, an E-Selectin Inhibitor, vs Placebo to Reduce GI Toxicity in Patients with Multiple Myeloma Undergoing Autologous Hematopoietic Cell Transplant

Introduction: High-dose Melphalan with autologous hematopoietic cell transplant (ASCT) plays a pivotal role in treating multiple myeloma (MM), but is associated with high rates of GI toxicity. Data suggest chemotherapy-initiated epithelial injury leads to inflammatory signaling and upregulation of the adhesion molecule, E-selectin, on vascular endothelium. This promotes inflammatory cell trafficking to sites of epithelial injury leading to further immune-mediated GI epithelial injury. Uproleselan (upro) is a synthetic, competitive E-selectin antagonist. Pre-clinical studies have shown upro+chemotherapy reduced GI toxicity in mice by blocking secondary migration of inflammatory macrophages to GI epithelium. Subsequent clinical trials evaluating upro+chemotherapy in AML showed reduced GI toxicities vs historical controls.

Methods: This was a Phase 2, single-center, randomized, double-blind, placebo-controlled trial of patients undergoing melphalan-conditioned (200mg/m2) ASCT for MM, randomized 1:1 to prophylactic upro+standard of care (SoC) vs placebo+SoC. The primary objective was to demonstrate superiority of upro+SoC to reduce mean diarrhea severity (CTCAE v5.0) during days 1-14 post-ASCT. Secondary endpoints included patient reported outcomes (PRO) of GI-related quality of life (QoL) (NCI PRO-CTCAE v1.0), Bristol Stool Scale (BSS), alternative GI toxicities and metrics of healthcare resource utilization. Exploratory sensitivity analyses of the primary endpoint evaluated diarrhea severity on days 1-10, 1-7 and 3-10 post-ASCT. Significance level of p< 0.2 was predefined for all endpoints.

Results: Fifty adults with MM enrolled from 5/2021-10/2022. Demographics were similar across arms. Over days 1-14 post-ASCT, a lower mean diarrhea severity score (1.07 vs 1.19, 95% CI -0.28; 0.04, p=0.34) and lower incidence of >Grade 2 diarrhea (odds ratio [OR] 0.61, 95% CI 0.35; 1.07, p=0.26) were observed favoring upro+SoC, but neither met significance level of p< 0.2. However, PRO QoL survey at day +8 post-ASCT showed reduced GI related symptoms in 6/20 (30%) domains (p=0.07-0.14) and reduced incidence of severe diarrhea by BSS (32% vs 42%, OR 0.63, 95% CI 0.44; 0.91, p=0.10), both favoring upro+SoC. Time to 1st antibiotics was delayed with upro+SoC (9.96 vs 8.56 days, p=0.07). Exploratory analysis of diarrhea severity on days 1-10, 1-7 and 3-10 post-ASCT showed lower mean diarrhea severity score favoring upro+SoC that did not reach significance (p=0.23, p=0.29 and p=0.23); while incidence of >Grade 2 diarrhea over those times were all significantly lower favoring upro+SoC (p=0.11, p=0.02 and p=0.14). Time to neutrophil engraftment and response rates were similar.

Conclusions: In this randomized, controlled trial, upro+SoC prior to melphalan-conditioned ASCT in MM did not meet its primary endpoint but met key secondary endpoints of reduced >Grade 2 diarrhea, reduced severe diarrhea by BSS and improved patient reported QoL, vs placebo+SoC. Further studies are needed to verify these observations.