Novel CELMoD Agent Demonstrates Early Promise in Relapsed/Refractory Myeloma

Lilly Wong, MD

The novel oral cereblon E3 ligase modulator (CELMoD) agent CC-92480 in combination with dexamethasone was found to be pharmacologically active with immunomodulatory activity at all doses as treatment of patients with relapsed/refractory multiple myeloma, according to findings from part 1 of the ongoing phase 1 CC-92480-MM-001 clinical trial (NCT03374085).

CC-92480 induces rapid degradation of the transcription factors Ikaros and Aiolos, which leads to apoptosis of the myeloma cells and immune-stimulatory effects. This innovative phase 1 study design evaluated the effects of a broad range of CC-92480 doses and schedules.

The trial utilized an intensive biomarker sampling program to characterize the pharmacodynamic (PD) changes, and peripheral blood and bone marrow aspirate were obtained from patients who were enrolled to part 1 of the dose-escalation study for pharmacokinetics (PK) and biomarker analysis. These findings were shared during a presentation at the 2020 American Society of Hematology (ASH) Annual Meeting, which explored the effects of PD with a focus on modulation of immune cell subsets.

The findings demonstrated a dose-dependent PK that correlated with a dose-dependent Aiolos and Ikaros degradation and recovery. Aiolos degradation was maximized with 1 mg treatment given for 10 of 14 days, but a longer break for recovery was required. The break was extended to 7 days, and 2 schedules with a 7-day break were explored. With a 7-days-on/7-days-off treatment schedule, the 7-day break was sufficient for Ikaros recovery, but patients required longer treatment to prevent the rebound of the serum light chains. The investigators then explored a 21 out of 28 days treatment schedule, and the continuous dosing of this treatment regimen led to sustained decreases in myeloma light chains.

Overall, continuous dosing with CC-92480 in combination with dexamethasone achieved a sustained decrease in myeloma paraproteins, and the 1-mg dose for 21 out of 28 days was selected as the recommended phase 2 dose and schedule.

Most patients in the study had low B-cell counts prior to the start of treatment, with a median of 8.5 cells/μL, and there was a significant decrease during treatment, for a median of 1 cell/μL. Continuous dosing with at least 0.6 mg maximized the B-cell changes during the treatment break, and this was also seen with the intermittent schedule at a dose greater than 1 mg.

Natural killer (NK) cell proliferation was observed at all doses with a peek occurring at approximately 1 week post-treatment regardless of the schedule. CC-92480 promoted NK cell proliferation in patients, including those who received daratumumab (Darzalex) in their last treatment regimen. On a 21 out of 28 days schedule, NK cell proliferation increased, and this coincided with a moderate decrease in NK cell counts. Similar observations were noted with other schedules. Although this effect may be due to trafficking, an additional analysis will be performed in part 2 of the study for confirmation.

A dosing schedule–dependent increase was observed in CD3-positive T-cell proliferation during treatment, and an increase was also noted in T-cell activation by human leukocyte antigen-DR isotope positivity for both CD4- and CD8-positive T cells. A return to baseline was observed during the 7-day break in the first cycle.

CC-92480 also induced a shift in T cells from naïve to effector phenotype. A modest increase in regulatory T cells was also observed, especially with the 1.0-mg dose and a trend toward baseline was reported during the 7-day break.

Clinical responses were observed at the 1.0-mg dose with both the 10 out of 14-day times 2 schedule and the 21 out of 28 days schedule. At the 1.0-mg dose, clinical response was associated with a higher percentage of proliferating CD4- and CD8-positive T cells in cycle 1. Among the population that responded compared with the non-responders, maximum T-cell proliferation was observed with a 2.5-fold increase for CD4-positive T cells and a 3-fold increase for CD8-positive T cells.

“The intense biomarker plan enabled the dose- and schedule-dependent dynamics of immunomodulation to be described,” said lead author Lilly Wong, MD, of Bristol Myers Squibb, during the ASH presentation. “The dynamic changes of immune cell subsets in the peripheral blood occurred in concert with the Ikaros and Aiolos degradation, suggesting that the immune profiles may be modified and optimized by dosing schedule. These data provide rationale to further explore different doses and schedules of CC-92480 in combination with immunomodulating therapies.”

These findings will be confirmed in part 2 of the clinical trial, which is currently enrolling and remains ongoing.

_Reference

_{Wong L, Lamba M, Nunez MDJ, et al. Dose- and scheduled-dependent immunomodulatory efficacy of the noel cereblon E3 ligase modulator agent CC-92480 in patients with relapsed/refractory multiple myeloma. Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020; Virtual. Abstract 2295.}