Promise of Immune Therapies in Multiple Myeloma

There has been major progress in the treatment of multiple myeloma (MM) in the past 15 years with the bench-to-bedside translation of novel agents targeting the tumor in its microenvironment, including the proteasome inhibitors bortezomib, ixazomib, and carfilzomib; the immunomodulatory drugs thalidomide, lenalidomide, and pomalidomide; the histone deacetylase inhibitor panobinostat; and the monoclonal antibodies daratumumab and elotuzumab.1,2 As a direct result, overall survival in MM has been extended at least three- to four-fold. The most promising strategies for additional progress include personalized medicine and immune therapies. Precision medicine has been challenging in MM because of its complex genetic profile, with ongoing genomic evolution underlying relapse of disease.3 The most commonly mutated pathway is RAS-Raf-MAPK signaling, and attempts to block this cascade with single or targeted agents have achieved only transient responses.4 Importantly, venetoclax targeting Bcl-2 together with bortezomib achieves responses in the majority of patients with t(11;14) translocation and likely represents the first personalized medicine in MM.5 Both basket and umbrella trials will further evaluate targeted therapies, alone and in combination, in MM. After decades of preclinical studies and clinical trials, immune therapies have come of age in MM, as reviewed by Baljevic and Holstein in this issue of the Journal of Oncology Practice.6 Immune-based strategies have the potential to overcome the intrinsic and ongoing evolving genetic complexity in MM. The anti-CD38 monoclonal antibody daratumumab, alone or in combination with lenalidomide/dexamethasone, bortezomib, or pomalidomide/dexamethasone, has been approved by the U.S. Food and Drug Administration (FDA) to treat relapsed MM and can achieve minimal residual disease negativity, even in advanced disease.7-9 Although daratumumab has an acceptable therapeutic index, CD38 is broadly expressed in endothelial cells, activated blood and immune cells, and hematopoietic progenitor cells, and lowering of blood counts and of normal immunoglobulins can be observed with long-term use. In phase III trials in relapsed MM, daratumumab/lenalidomide/dexamethasone and daratumumab/bortezomib/dexamethasone were superior to lenalidomide/dexamethasone and bortezomib/dexamethasone, respectively. However, in North America, lenalidomide/bortezomib/dexamethasone is commonly used as initial therapy,10 and relapsed MM is therefore refractory to both lenalidomide and bortezomib. Because the activity of