PF559 IBERDOMIDE (CC‐220) IS PHARMACODYNAMICALLY ACTIVE AND HAS DOSE‐DEPENDENT IMMUNOSTIMULATORY ACTIVITY IN RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS IRRESPECTIVE OF PRIOR IMID DRUG TREATMENT
Authors: Amatangelo M. , Gaudy A. , Bjorklund C. , Wang M. , Couto S. , Pierceall W. , van de Donk N.W. , Lonial S. , Popat R. , Zonder J.A. , Minnema M.C. , Larsen J. , Sonneveld P. , Nguyen T.V. , Hong K. , Biyukov T. , Thakurta A. 
Published: June 2019

Background:

Iberdomide (IBER) is a novel cereblon (CRBN) E3 ligase modulatory compound (CELMoD) that is being investigated as monotherapy, in combination with dexamethasone (DEX), and in combination with DEX and daratumumab or bortezomib in a phase 1b/2a dose‐escalation study in relapsed/refractory multiple myeloma (RRMM). IBER modulates CRBN, which induces ubiquitination of Aiolos, Ikaros and ZFP91, increases their proteasome‐dependent degradation, and thereby inhibits myeloma cell growth. IBER binds more potently to CRBN and is more efficient at degrading Aiolos and Ikaros than the immunomodulatory agents (IMiDs) lenalidomide (LEN) and pomalidomide (POM) and it can overcome IMiD drug resistance in pre‐clinical models.

Aims:

To determine if IBER is pharmacodynamically (PD) active in multiple myeloma patients refractory to POM and/or LEN, and to establish pharmacokinetic (PK)/PD and PD/dose relationships.

Methods:

As of Jan 11, 2019, 83 patients received IBER as monotherapy or in combination with DEX; 61 (74%) were LEN refractory and 47 (57%) were POM refractory. Longitudinal immunohistochemistry (IHC) data on CRBN, Aiolos, Ikaros and ZFP91 expression was obtained from bone marrow samples from 14 patients dosed with 0.3–0.9 mg IBER daily ± DEX. PD analysis of immune activity by TruCulture® (n = 45) and by peripheral blood flow cytometry (n = 60) was completed on a subset of patients dosed up to 1.0 mg IBER ± DEX. A population PK approach was used to estimate exposure (area under the concentration curve over the 24 hr dosing interval [AUCτ]) on 59 patients dosed up to 1.0 mg IBER ± DEX.

Results:

IBER AUCτ increased in a dose‐proportional manner in RRMM patients over the dose range 0.3–1.0 mg (22.4–65.31 ng∗hr/mL, respectively). In patient biopsies analyzed to date, CRBN expression was observed in all tumors by IHC at baseline and did not significantly change while on‐treatment. Furthermore, no significant decrease in baseline CRBN expression was observed in patients refractory to POM. In MM cells, significant decreases in Aiolos (median 37% decrease, P < 0.001), Ikaros (median 12% decrease, P = 0.006), and ZFP91 (median 47% decrease, P < 0.001) protein expression were observed on‐treatment across all dose levels; these decreases were unrelated to levels of CRBN expression at screening or prior LEN or POM refractoriness. In TruCulture® samples, dose‐dependent increases were observed in IL‐2 and IFN‐γ, with median increases of 78% and 66%, respectively, 5 hours post 0.9 mg dose of IBER. A dose‐ and exposure‐dependent decrease in B‐cells was detected (median 74% decrease at cycle 2 day 15, IBER 0.9 mg). These observations are consistent with the proposed IBER mechanism of action. Immunoprofiling showed significant increases in total and proliferating NK cells in RRMM patients treated with IBER, and a dose‐dependent increase in proliferating, activated, and effector memory T‐cells. These trends were consistent in RRMM patients treated with IBER monotherapy and in combination with DEX.

Summary/Conclusion:

These translational analyses from IBER treated RRMM patients indicate it is pharmacodynamically active at the lowest dose (0.3 mg) and exhibits dose‐ and exposure‐dependent immunostimulatory activity, supporting further dose‐escalation beyond 1.0 mg, which is currently ongoing. These results also suggest that prior refractoriness to LEN or POM is not associated with significant loss of CRBN or IBER PD activity, supporting continued investigation of IBER in RRMM patients refractory to IMiD drugs.