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Iberdomide (IBER), a potent oral cereblon E3 ligase modulator (CELMoD®) agent with enhanced tumoricidal and immune-stimulatory effects versus immunomodulatory (IMiD®) agents, has shown marked synergy with dexamethasone (DEX) and other standard myeloma treatments in preclinical models. IBER is being evaluated with various treatment combinations in patients (pts) with relapsed/refractory multiple myeloma (RRMM) in the phase 1/2 study CC-220-MM-001 (NCT02773030). Results from the dose expansion of IBER+DEX in pts with heavily pretreated, triple-class exposed (≥1 IMiD agent, ≥1 proteasome inhibitor PI, and ≥1 CD38 monoclonal antibody mAb) RRMM are reported here. Key eligibility criteria were: RRMM; ≥3 prior lines of therapy, including lenalidomide, pomalidomide, a PI, a glucocorticoid, and a CD38 mAb; progressive disease (PD) within 60 days of last myeloma therapy; and refractoriness to an IMiD agent, a PI, a glucocorticoid, and a CD38 mAb. Pts who had received prior anti-BCMA therapy were included in a separate cohort. Oral IBER (at the recommended phase 2 dose of 1.6 mg) was given on days (D) 1–21, plus DEX (40 mg; 20 mg if >75 years of age) on D1, 8, 15, and 22 of each 28-day cycle. The primary endpoint was to determine efficacy as overall response rate (ORR). Secondary endpoints included further efficacy and safety assessments; health-related quality of life (HRQoL) was an exploratory endpoint. As of June 2, 2021, 107 pts had received IBER+DEX with a median age of 64 (44–83) years and a median time since initial diagnosis of 6.9 (1.6–24.5) years; 25.2% and 29.9% of pts had extramedullary plasmacytomas and high-risk cytogenetics, respectively. Median number of prior regimens was 6 (3–23), and prior therapies included autologous stem cell transplantation (78.5%), IMiD agents (100%), PIs (100%), and CD38 mAbs (100%); 99.1% of pts were refractory to last myeloma regimen and 97.2% of pts had triple-class refractory disease. Median follow-up was 7.69 (0.5–17.5) months; median number of cycles received was 4 (1–17), with 12.1% pts continuing treatment and 69.2% pts discontinuing due to PD. ORR was 26.2%, with 0.9% stringent complete responses, 7.5% very good partial responses, and 17.8% partial responses; clinical benefit rate was 36.4% and disease control rate 79.4%. Median duration of response was 7.0 (4.5–11.3) months, median progression-free survival 3.0 (2.8–3.7) months, and median overall survival 11.2 (9.0–not reached) months. Similar response rates (ORR=25%) were reported among pts who had prior anti-BCMA therapy (N=24). Overall, 82.2% of pts had grade (Gr) 3/4 treatment-emergent adverse events (TEAEs). Most frequent hematologic Gr 3/4 TEAEs were neutropenia (44.9%; 4.7% febrile neutropenia), anemia (28.0%), thrombocytopenia (21.5%), and leukopenia (20.6%); 27.1% of pts had Gr 3/4 infections with 10.3% reporting Gr 3/4 pneumonia. Occurrence of other Gr 3/4 non-hematologic TEAEs was generally low. IBER dose interruptions and reductions due to TEAEs occurred in 52.3% and 18.7% of pts, respectively; 4.7% of pts discontinued due to TEAEs. No pt discontinued IBER due to neutropenia. Overall, HRQoL was maintained in these pts. IBER+DEX showed promising efficacy and a manageable safety profile in pts with heavily pretreated, triple-class refractory RRMM, as well as in pts who had received prior anti-BCMA therapy. These results support further development of IBER in combination regimens in MM, including initiation of phase 3 trials.
Donk et al. (Fri,) studied this question.