Tasquinimod, an S100A9 Inhibitor, in Combination with Ixazomib, Lenalidomide, and Dexamethasone for Relapsed and Refractory Multiple Myeloma
Authors: Vogl Dan T. , Nefedova Yulia , Wileyto E. Paul , Nguyen Chau , Diaczynsky Cynthia , Strakovsky Inna , Bondesson Eva , Tuvesson Helen , Vahtola Erik , Cohen Adam D. , Susanibar-Adaniya Sandra , Waxman Adam , Kapur Shivani , Garfall Alfred L. , Stadtmauer Edward A. 
Published: December 2024

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 (Lin C, EHA 2020: EP896). A previous trial showed that tasq 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 relapsed or refractory multiple myeloma (RRMM) (ASCO 2023, Abstract 8042; NCT04405167). In 10 intensively pretreated pts receiving single-agent tasq, we identified a recommended phase 2 dose (RP2D) of 1 mg daily (qd) after a 1 week (wk) run-in at 0.5 mg qd. Single-agent tasq led to stabilization of disease in 3 pts but no objective responses. We now report preliminary results of tasq in combination with IRd.
Methods: In dose escalation, pts were refractory to, intolerant of, or with contraindication to len, pomalidomide (pom), bortezomib, carfilzomib (cfz), and a CD38 monoclonal antibody. In dose expansion, pts were refractory to their most recent Imid/PI combination or refractory to an Imid, a PI, and an anti-CD38 monoclonal antibody (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 the dose escalation cohorts, pts received full doses of ixa (4 mg days 1/8/15), len (25 mg days 1-21, with adjustments for renal dysfunction), and dex (40 mg qwk), but in the dose expansion cohort, starting doses of ixa, len, and dex could be reduced per investigator discretion.
Results: 11 pts have received tasq with IRd at dose level 1 (3 pts) and dose level 2 (8 pts, 3 in dose escalation and 5 in dose expansion). Median age was 66 y (range 52-75); 81% were male; 18% were African American and 82% Caucasian. Pts had received a median of 7 prior lines of therapy (range 3-13), and all were triple-class refractory and penta-exposed, with 82% (9 pts) refractory to their most recent Imid/PI combination. 82% had received prior BCMA-directed therapy (45% CAR T cells and 36% bispecific T cell engagers).
During dose escalation, no dose limiting toxicities were observed, and dose level 2 was selected as the RP2D of tasq in combination with IRd. Among all 11 pts, the most common treatment-emergent adverse events (TEAEs) were fatigue (9 pts: grade [gr] 3 in 1 pt), pain (7 pts: all gr 1/2), nausea/vomiting (5 pts: all gr 1/2), respiratory infection (5 pts: 2 gr 3, 1 gr 5), constipation (4 pts, all gr 1/2), edema (3 pts: all gr 1/2), insomnia (3 pts: 1 gr 3), dyspepsia/gastritis (3 pts: 1 gr 3), and weight loss (3 pts: all gr 1/2).
Among all 11 pts, there was 1 partial response (PR) and 3 minimal responses (MR). Among the 9 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 19.8 months, and 2 MRs (1 transient and 1 still ongoing after 3 months).
Conclusions: Tasquinimod, an S100A9 inhibitor, is well tolerated in combination with IRd and has anti-myeloma activity, as evidenced by three clinical responses in patients previously refractory to Imid/PI combination therapy. The RP2D of tasquinimod in combination with IRd is 1 mg daily after a 1-week run-in period at 0.5 mg daily. Enrollment continues to tasquinimod with IRd, with a goal of enrolling 6 more patients who are refractory to their most recent Imid/PI combination therapy.