Clinical activity of novel targeting of S100A9 with tasquinimod for relapsed and refractory multiple myeloma (RRMM).

7555 Background: S100A9, a protein produced by myeloid-derived suppressor cells 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 (Cancer Res Commun 2023;3(3):420) and improved progression-free survival in prostate cancer patients (pts) (JCO 2016;34(22):2636-43). We previously reported preliminary results of a phase 1 trial of tasq alone and in combination with ixazomib (ixa), lenalidomide (len), and dexamethasone (dex) (IRd) in pts with RRMM (JCO 2023;41(16)suppl:8042; NCT04405167). For single-agent tasq, the recommended phase 2 dose (RP2D) was 1 mg daily (qd) after a 1 week (wk) run-in at 0.5 mg qd. We now report updated results of tasq in combination with IRd. Methods: In dose escalation, pts were refractory, intolerant, or contraindicated to len, pomalidomide, bortezomib, carfilzomib, and an anti-CD38 monoclonal antibody. In dose expansion, pts were refractory to the most recent Imid/PI combination or triple-class refractory. Tasq was given in 28-day cycles at 1 mg daily with either a 2 wk run-in (dose level 1: 0.25 mg qd x1 wk then 0.5 mg qd x1 wk) or a 1 wk run-in (dose level 2: 0.5 mg qd x1 wk). In dose escalation, pts received full doses of ixa (4 mg days 1/8/15), len (25 mg days 1-21, adjusted for renal dysfunction), and dex (40 mg qwk), but in dose expansion, doses of ixa, len, and dex were reduced per investigator discretion. Results: 16 pts received tasq with IRd at dose levels 1 (3 pts) and 2 (13 pts: 3 in escalation, 10 in expansion). Median age was 67 y (range 52-81); 75% were male; 19% were African American and 81% Caucasian. Pts had received median 7 prior lines of therapy (range 3-19), and all were triple-class refractory, with 81% (13 pts) refractory to their most recent Imid/PI combination. In dose escalation, no dose limiting toxicities were observed, and dose level 2 was the RP2D of tasq with IRd. The most common treatment-emergent adverse events were fatigue (10 pts: grade [gr] 3 in 1 pt), pain (9 pts: 0 gr ≥3), respiratory infection (9 pts: 4 gr 3, 2 gr 5), nausea/vomiting (8 pts: 0 gr ≥3), dyspepsia/gastritis (5 pts: 1 gr 3), and thrombocytopenia (5 pts: 1 gr 3, 3 gr 4). Among all 16 pts, there was 1 partial response (PR) and 7 minimal responses (MR). Among the 13 pts who were previously refractory to their most recent Imid/PI combination and would therefore not be expected to respond to the IRd backbone, there was 1 PR (lasting 20 months) and 5 MRs (lasting 1, 1, 2, 2, and 7 months). Conclusions: Tasquinimod, an S100A9 inhibitor, is well tolerated in combination with IRd and has anti-myeloma activity, as evidenced by responses in patients previously refractory to Imid/PI combination therapy. Further study is warranted of tasquinimod in combination with standard myeloma therapies. Clinical trial information: NCT04405167 .