Cobimetinib Alone and Plus Venetoclax With/Without Atezolizumab in Patients With Relapsed/Refractory Multiple Myeloma

• Published in: Clinical lymphoma, myeloma and leukemia myeloma and leukemia, 2023-01, Vol.23 (1), p.e59-e70
• Main Authors: Schjesvold, Fredrik, Paiva, Bruno, Ribrag, Vincent, Rodriguez-Otero, Paula, San-Miguel, Jesus F., Robak, Pawel, Hansson, Markus, Onishi, Maika, Hamidi, Habib, Malhi, Vikram, Dail, Monique, Javery, Apurva, Ku, Grace, Raab, Marc S.
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - adverse effects; B-cell lymphoma-2; B-cell lymphoma-2, Programmed death-ligand 1; Biomarker; Bridged Bicyclo Compounds, Heterocyclic - adverse effects; Clinical Medicine; Humans; Immunotherapy; Klinisk medicin; Mitogen-activated protein kinase pathway; Mitogen-activated protein kinase pathway, Immunotherapy; Multiple Myeloma - drug therapy; Multiple Myeloma - etiology; Programmed death-ligand 1; Proto-Oncogene Proteins c-bcl-2
• ISSN: 2152-2650; 2152-2669
• DOI: 10.1016/j.clml.2022.10.006

•Cobi, cobi-ven and cobi-ven-atezo were safe and tolerable in patients with R/R MM.•Cobi-ven and cobi-ven-atezo had moderate activity in all-comers.•Cobi-ven and cobi-ven-atezo had higher activity in patients with t(11;14)+ MM. Mitogen-activated protein kinase pathway mutations are present in >50% of patients with relapsed/refractory (R/R) multiple myeloma (MM). MEK inhibitors show limited single-agent activity in R/R MM; combination with B-cell lymphoma-2 (BCL-2) and programmed death-ligand 1 inhibition may improve efficacy. This phase Ib/II trial (NCT03312530) evaluated safety and efficacy of cobimetinib (cobi) alone and in combination with venetoclax (ven) with/without atezolizumab (atezo) in patients with R/R MM. Forty-nine patients were randomized 1:2:2 to cobi 60 mg/day on days 1–21 (n = 6), cobi 40 mg/day on days 1–21 + ven 800 mg/day on days 1–28 with/without atezo 840 mg on days 1 and 15 of 28-day cycles (cobi-ven, n = 22; cobi-ven-atezo, n = 21). Safety run-in cohorts evaluated cobi-ven and cobi-ven-atezo dose levels. Any-grade common adverse events (AEs) with cobi, cobi-ven, and cobi-ven-atezo, respectively, included diarrhea (33.3%, 81.8%, 90.5%) and nausea (16.7%, 50.0%, 66.7%); common grade ≥3 AEs included anemia (0%, 22.7%, 23.8%), neutropenia (0%, 13.6%, 38.1%), and thrombocytopenia (0%, 18.2%, 23.8%). The overall response rate for all-comers was 0% (cobi), 27.3% (cobi-ven), and 28.6% (cobi-ven-atezo), and 0%, 50.0%, and 100%, respectively, in patients with t(11;14)+. Biomarker analysis demonstrated non-t(11;14) patient selection with NRAS/KRAS/BRAF mutation or high BCL-2/BCL-2-L1 ratio (>52% of the study population) could enrich for responders to the cobi-ven combination. Cobi-ven and cobi-ven-atezo demonstrated manageable safety with moderate activity in all-comers, and higher activity in patients with t(11;14)+ MM, supporting a biomarker-driven approach for ven in MM. This phase IB/II trial evaluated safety and efficacy of cobimetinib alone and in novel combinations with venetoclax with/without atezolizumab in patients with relapsed/refractory multiple myeloma. Forty-nine patients were enrolled. Cobimetinib alone and in combination with venetoclax with/without atezolizumab was determined to be safe and tolerable; anti-tumor activity was moderate overall but higher in patients with translocation t(11;14).