CELMoD Combinations Effective in Treating Relapsed/Refractory Multiple Myeloma

Iberdomide, an oral potent novel cereblon E3 ligase modulator (CELMoD), in combination with other agents demonstrated an acceptable toxicity profile and promising clinical activity in patients with relapsed/refractory multiple myeloma (MM), according to a study presented at the ASH Annual Meeting & Exposition.

The phase I/II CC-220-MM-001 study is evaluating dose escalations of iberdomide with different treatment combinations in cohorts of patients with relapsed/refractory MM, including iberdomide in combination with dexamethasone and daratumumab (IbrDd) and with bortezomib and dexamethasone (IbrVd).

Eligible patients had received two or more prior therapies in the IbrDd cohort and one or more therapies in the IbrVd cohort, containing at least lenalidomide or pomalidomide, as well as a proteasome inhibitor. Patients had experienced disease progression on or within 60 days of last MM therapy.

Escalating doses of iberdomide were given orally ranging from 1.0 mg to 1.6 mg. In the IberDd cohort (n=19; median age, 66 years; range, 40-77 years), patients received daratumumab 16 mg/kg plus dexamethasone weekly; in the IberVd cohort (n=21; median age, 65 years; range, 47-81 years), patients received bortezomib 1.3 mg/m2 plus dexamethasone weekly.

The maximum tolerated dose and recommended phase II dose were not reached in either treatment cohort. Median follow-up was five months (range, 0-14 months) in the IberDd cohort and three months (range, 0-11 months) in the IberVd cohort. Patients received a median of five treatment cycles (range, 1-14 cycles) in the IberDd group and 4.5 cycles (range, 1-17 cycles) in the IberVd group.

Grade 3/4 treatment-related adverse events occurred in 14 (78%) patients treated with IberDd and in 13 (65%) treated with IberVd, the most common of which were neutropenia (50%), leukopenia (22%), and anemia (22%) with IberDd and neutropenia (20%) and thrombocytopenia (20%) with IberVd. One patient in the IberDd cohort receiving iberdomide 1.2 mg had grade 4 neutropenic sepsis. Six (33%) and four (20%) patients, respectively, required iberdomide dose reductions.

The IberDd cohort included 12 (63%) daratumumab-refractory patients and 11 (58%) quadruple-class-refractory patients. In this arm, the overall response rate (ORR) was 35%, including two very-good partial responses (VGPRs) and four partial responses (PRs). The clinical benefit rate (CBR) was 47%, and the disease control rate (DCR) was 88%.

The IberVd cohort included 16 patients (76%) who were refractory to proteasome inhibitors, nine (43%) who were bortezomib-refractory, and 10 (48%) who were quadruple-class-refractory. In this cohort, the ORR was 50%, including one complete response, three VGPRs, and six PRs. The CBR was 65%, and the DCR was 85%.

Responses for both treatment regimens were observed regardless of daratumumab- and bortezomib-refractory status. Median time to response was 4.1 weeks with IberDd (range, 4.1-12.0 weeks) and 4.9 weeks (range, 3.0-13.1 weeks) with IberVd. Median duration of response was not reached in either cohort.

“These results support the further development of iberdomide-based regimens in MM,” the researchers concluded, noting that phase III trials are planned to further evaluate these combinations.