ISY-29-1 - Scientific basis of new targeted therapies for myeloma

Abstract

Based on positive clinical benefits with new agents, patients with multiple myeloma (MM) should receive the most effective therapy based on proteasome inhibitors and/or immunomodulatory drugs (IMiDs) as backbone medication to achieve CR with the goal of extended survival. Proteasome inhibitors perturb protein handling pathways to elicit ER stress and disrupt survival signaling. Panobinostat, a pan-deacetylase inhibitor, synergistically augments the interference with protein degradation and thereby MM cell death with proteasome inhibitors, while altering gene expression. IMiDs have multiple proposed mechanisms of action, including degradation of IKZF1 and IKZF3 to decrease IRF4 and cMyc, pro-survival mediators, in MM cells. MM cells alter their surrounding microenvironment through bone destruction, angiogenesis and immune paresis in bone marrow where they colonize, which in turn favors tumor growth and survival, thereby forming a progressive vicious cycle between tumor progression and the microenvironmental alteration. These new agents also target the tumor microenvironment to disrupt the vicious cycle. Besides, proteasome inhibitors and panobinostat exert a bone anabolic effect via suppression of osteoclast activity and stimulation of osteoblast differentiation. New generation IMiDs, lenalidomide and pomalidomide, have immunomodulatory activity to improve immune function and thereby MM cell killing. Of note, these IMiDs enhance ADCC activity against MM cells with anti-CS1 and anti-CD38 therapeutic monoclonal antibodies, and checkpoint blockade-mediated MM cytotoxicity with anti-PD-1 antibody, yielding better outcomes. Due to the incurable nature of MM, however, the development of newer agents is ongoing. Upcoming novel molecular targeting agents with different modes of action and immunotherapeutic agents will be integrated into MM treatment regimens with a great therapeutic impact, and further evolution of the treatment paradigm for MM is eagerly anticipated.