Combination Targeted Therapies Under Study in Myeloma
Posted: Monday, April 15, 2019
Despite recent improvements in survival for patients with multiple myeloma, there is still an unmet need for therapies that target particular drivers of the disease. Vijay G. Ramakrishnan, PhD, of the Mayo Clinic, Rochester, Minnesota, and colleagues investigated several combinations of compounds in development that appear to mediate resistance via synergistic activity in myeloma plasma cells. Their research was published in Haematologica.
Mutations in KRAS, NRAS, and BRAF are common in multiple myeloma, affecting 50% of patients at diagnosis and more than 70% at relapse. Previous studies have found that targeting mutated RAS/RAF with MEK inhibitor monotherapy is largely ineffective. However, when Dr. Ramakrishnan and colleagues combined the MEK inhibitor selumetinib with the histone deacetylase (HDAC) inhibitor panobinostat, the duo induced synergistic apoptosis in RAS/RAF-mutated multiple myeloma cell lines. Dependent on the levels of the proapoptotic protein BIM, the combination was specifically active in cell lines with more BIM:MCL-1 complexes at baseline.
Additionally, cell lines that were resistant to the selumetinib/panobinostat combination had more BIM:BCL-2 complexes. By combining the BH3 mimetic venetoclax with panobinostat, these resistant cell lines were synergistically killed. The researchers also demonstrated that in these same myeloma cell lines, concomitant inhibition of HDAC1 and HDAC2 (with entinostat or romidepsin) was “sufficient to synergize” with either MEK or BCL2 inhibition. These drug combinations also effectively killed plasma cells from patients with myeloma ex vivo.
“Given the preponderance of RAS/RAF mutations, and the fact that [venetoclax] has demonstrated clinical efficacy in relapsed/refractory multiple myeloma, these drug combinations hold promise as biomarker-driven therapies,” concluded the investigators.
Disclosure: The study authors’ disclosure information may be found at haematologica.org.