Background: S100A9, a protein produced by myeloid-derived suppressor cells (MDSCs) in the bone marrow microenvironment, promotes multiple myeloma (MM) progression and confers therapeutic resistance. Tasquinimod (tasq), an oral S100A9 inhibitor, has pre-clinical anti-myeloma effects alone and combined with proteasome inhibitor (PI) and immunomodulator (Imid) therapy (Lin C, EHA 2020: EP896). Tasq previously improved PFS in prostate cancer patients (pts) (JCO 2016;34(22):2636-43). We are conducting a phase 1 trial (NCT04405167) of tasq as a single agent and in combination with ixazomib (ixa), lenalidomide (len), and dexamethasone (dex) (IRd) in pts with RRMM. Methods: We enrolled pts with RRMM refractory to, intolerant of, or with contraindication to len, pomalidomide (pom), bortezomib, carfilzomib (cfz), and a CD38 monoclonal antibody. Tasq was given in 28-day cycles as shown below, with a 3+3 dose escalation scheme. For combination therapy, pts received ixa (4 mg days 1/8/15), len (25 mg days 1-21, with adjustments for renal dysfunction), and dex (40 mg qwk). Results: Of 15 pts, median age was 70y (range 56-84); 53% were male; 27% were African American and 73% Caucasian. Pts had received a median of 8 prior lines of therapy (range 4-17), and all were refractory to ≥1 Imid, 87% to ≥1 PI, and 100% to a CD38 mAb, with 87% triple class refractory and penta-exposed. 10 pts received single-agent tasq at dose levels 1 (3 pts), 2 (3 pts), and 3 (4 pts). The most common treatment-emergent adverse events (TEAEs) were fatigue (all grade [gr] 1/2), anemia (5 pts, gr 3 in 2), anorexia (5 pts, gr 3 in 2), pain (5 pts, all gr 1/2), nausea/vomiting (4 pts, all gr 1/2), and neuropathy (3 pts, all gr 1/2). No dose-limiting toxicities (DLTs) were observed, but at dose level 3, 2 pts stopped for intolerable toxicities, and we identified dose level 2 as the single-agent MTD. 5 pts have received tasq with IRd at dose levels 1 (3 pts) and 2 (2 pts). Gr > = 3 TEAEs were gr 4 thrombocytopenia in 1 pt (improved with dose reductions of ixa and len), gr 3 insomnia in 1 pt, and gr 5 COVID pneumonia in 1 pt. No tasq-related DLTs were observed. On single-agent tasq, 3 pts with progressive disease at study entry had stabilization of serum markers while on study. Of 5 pts on the IRd combination, 1 has had a partial response that is ongoing after 10 months, despite being previously refractory to ixa/pom and cfz/pom combinations. Conclusions: Tasquinimod, an S100A9 inhibitor, is well tolerated in pts with RRMM as a single-agent and in combination with IRd, with a single-agent MTD of 1 mg daily after a 1-week dose escalation. Tasq has anti-myeloma activity in combination with IRd, as evidenced by a partial response in a patient previously refractory to Imid/PI combination therapy. Enrollment continues to tasq with IRd at dose level 2. Clinical trial information: NCT04405167.