Iberdomide (IBER) in Combination with Dexamethasone (DEX) in Relapsed/Refractory Multiple Myeloma (RRMM): Results from the Anti-B-Cell Maturation Antigen (BCMA)-Exposed Cohort of the CC-220-MM-001 Trial

Introduction: IBER, a novel, oral cereblon E3 ligase modulator (CELMoD^®), has greater tumoricidal and immune-stimulatory effects compared with immunomodulatory drugs (IMiDs^®), and has shown marked synergy with DEX and other antimyeloma therapies in preclinical models. IBER is being investigated in the phase 1/2 CC-220-MM-001 (NCT02773030) and phase 3 EXCALIBER-RRMM (NCT04975997) studies with different treatment combinations in patients (pts) with RRMM. In phase 1 of CC-220-MM-001, IBER + DEX showed notable efficacy (overall response rate [ORR] 31.9%) and a manageable safety profile. Given the emergence of novel anti-BCMA therapies in RRMM, assessment of pts with prior anti-BCMA exposure is an important consideration. Here we report results from the dose-expansion phase of IBER + DEX in heavily pretreated, triple-class-exposed (including ≥ 1 IMiD agent, ≥ 1 proteasome inhibitor [PI], and ≥ 1 anti-CD38 monoclonal antibody [mAb]) pts with RRMM who had also received prior anti-BCMA therapy.

Methods: Eligible pts had RRMM, had received ≥ 3 prior lines of therapy (including lenalidomide or pomalidomide, a PI, an anti-CD38 mAb, and an anti-BCMA therapy) and had documented progressive disease (PD) on or within 60 days of their last antimyeloma therapy (documented PD if chimeric antigen receptor [CAR] T cell therapy was the last therapy). IBER 1.6 mg was given orally on days 1–21 of each 28-day cycle, plus weekly DEX (40 mg; 20 mg if > 75 years of age). The primary objectives were to determine preliminary efficacy (ORR) and safety.

Results: As of April 15, 2022, 38 pts had received IBER + DEX in the anti-BCMA-exposed cohort. Median age was 65 (range 50–78) years and median time since initial diagnosis was 7.8 (0.6–24.8) years. High-risk cytogenetics were present in 31.6% of pts (52.6% pts were not evaluable), and 23.7% of pts had extramedullary plasmacytomas. Median number of prior regimens was 7 (4–15). All pts were triple-class exposed. Prior anti-BCMA therapies included CAR T cell therapy (36.8%), antibody-drug conjugates (34.2%), and T-cell engagers (TCEs; 23.7%) (Table); 78.9% of pts were refractory to the last antimyeloma regimen and 84.2% were triple-class refractory. Median follow-up was 8.1 (range 1.5–24.2) months, with a median number of 3.5 (1–19) cycles received and 21.1% of pts continuing treatment. Discontinuation was due mainly to PD, reported in 68.4% of pts.

ORR (≥ partial response) was 36.8%, with 2 (5.3%) complete responses, 5 (13.2%) very good partial responses, and 7 (18.4%) partial responses. Clinical benefit rate (≥ minimal response) was 39.5%. Responses were observed regardless of prior anti-BCMA therapy (Figure; updated data will be presented at the congress). Median duration of response was 7.5 (95% confidence interval [CI] 3.2–not reached) months, median progression-free survival was 2.4 (95% CI 2.1–4.2) months, and median time to response was 1.4 (range 0.9–5.4) months.

Grade (Gr) 3/4 treatment-emergent adverse events (TEAEs) occurred in 30 (78.9%) pts and were mostly hematologic; most frequent (≥ 20% pts) were neutropenia (50.0%, with 5.3% cases of febrile neutropenia), anemia (28.9%), leukopenia (23.7%), and thrombocytopenia (21.1%). Gr 3/4 infections occurred in 23.7% of pts and included pneumonia (21.1%); the occurrence of other Gr 3/4 non-hematologic TEAEs was low and included hypokalemia, hypertension, and mood alterations (all 5.3%). Two (5.3%) deaths were reported (due to sepsis and PD) which were not considered related to study treatment. IBER dose interruptions and reductions occurred in 24 (63.2%) and 7 (18.4%) pts, respectively. No pts discontinued IBER due to TEAEs.

Immunophenotyping showed comparable immunodeficiency (low absolute B-cell counts, T-cell counts, and CD4:CD8 ratio) between anti-BCMA-exposed pts and triple-class-exposed pts without prior anti-BCMA exposure; this was more pronounced following TCE-based therapies. Importantly, IBER + DEX remained immune-stimulatory in this population, increasing T- and NK-cell proliferation and T-cell activation.

Conclusions: IBER + DEX showed encouraging efficacy and safety in pts with triple-class-exposed RRMM and prior anti-BCMA therapy. The results are comparable to those from Cohort D of the same study, which is assessing IBER + DEX in pts with triple-class refractory RRMM. These findings support further development of IBER in RRMM, including in anti-BCMA-exposed pts.