IberDd, IberVd Combinations Show Favorable Tolerability in Heavily Pretreated Relapsed/Refractory Multiple Myeloma

The combination of iberdomide (IBER) plus daratumumab and dexamethasone (IberDd) and the combination of IBER plus bortezomib and dexamethasone (IberVd) showed a favorable tolerability profile in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM), according to data to be presented at the virtual American Society of Hematology (ASH) conference on December 7, 2020.

The combinations also demonstrated promising clinical activity, even among patients refractory to the last prior regimen and previously exposed to IMiD agents, proteasome inhibitors (PIs), and CD38 antibodies.

Iberdomide is an oral, potent novel cereblon E3 ligase modulator agent with marked synergistic tumoricidal and immune-stimulatory effects in combination with bortezomib or daratumumab in preclinical models. The phase 1 and 2 study, CC-220-MM-001, evaluated the dose escalations of IBER with different treatment combinations in independent cohorts in patients with RRMM.

The iberdomide and dexamethasone cohort showed a favorable safety profile with promising efficacy and a selected IBER RP2D of 1.6 mg 21 or 28 days.

Eligible patients had received more than or equal to 2 prior regimens in the IberDd cohort, and more than or equal to 1 prior regimen in the IberVd cohort, containing at least lenalidomide or pomalidomide and a PI, and had experienced disease progression on or within 60 days of last MM therapy.

Escalating doses of IBER were given orally, in the IberDd cohort on days 1-21, with daratumumab on day 1, day 8, day 15, and day 22, day 1 and day 15, and day 1, of each 28-day cycle. As for the IberVd cohort, on days 1-14, with bortezomib on day 1, day 4, day 8, and day 11, and on day 1 and day 8 of each 21-day cycle. Dexamethasone was given weekly in both cohorts.

As of June 18, 2020, 19 patients had received IberDd and 21 patients had received IberVd. All patients were refractory to their last prior regimen, and exposure to prior regimens was heterogeneous. Median follow-up was 5 and 3 months, with 10 and 13 patients continuing on treatment, and median cycles received were 5 and 4.5 with IberDd and IberVd, respectively.

Grade 3 to 4 treatment-emergent adverse events (TEAEs) were reported in 14 patients with IberDd, and in 13 patients with IberVd. Most frequent grade 3-4 TEAEs of interest included neutropenia, leukopenia, and anemia with IberDd, and neutropenia and thrombocytopenia with IberVd. One patient had grade 4 neutropenic sepsis, with an occurrence of grade 3-4 non-hematological TEAEs was low in both cohorts.

Further, 1 patient had grade 2 infusion-related reaction with IberDd, and 3 patients had grade 1-2 peripheral neuropathy with IberVd.

Additionally, 6 and 4 patients had IBER dose reductions with IberDd and IberVd, respectively. In the IberDd cohort, with 63% daratumumab-refractory patients and 11 quad-class-refractory patients, the overall response rate (ORR) was 35% across all dosing groups. The clinical benefit rate was 47% and disease control rate was 88%. In the IberVd cohort, 76% PI-refractory patients, 43% bortezomib-refractory patients, and 48% quad-class refractory patients, the ORR was 50%, the clinical benefit rate was 65%, and the disease control rate was 85%.

The median time to response was 4.1 and 4.9 weeks, in both the IberDd and IberVd cohorts, respectively, with the median duration of response not being reached in both cohorts. Further, immune profiling showed dose-dependent decreases in B cells and increases in activated and differentiated T cells in both cohorts.

Immune-profiling data confirm that IBER and dexamethasone was pharmacodynamically active in triplet combination and not augmented by the addition of daratumumab or bortezomib. The study is ongoing with continued enrollment at the 1.6 mg dose level for both cohorts. Further, these results support the further development of IBER-based regimens in MM, with phase 3 trials planned to continue evaluating these combinations, according to the study.

REFERENCE

Myeloma/Amyloidosis: Therapy, excluding Transplantation; Novel Approaches for Relapsed/Refractory Myeloma and Amyloidosis. Poster presented at ASH 2020 Virtual Conference. December 7, 2020.