Turning Cold into Hot Myeloma

Mariateresa Fulciniti, PhD
Dana-Farber Cancer Institute

Anticancer drugs mediate their activity not only by direct cytostatic or cytotoxic effects but also stressing cancer cells in such a way that they become recognizable to the immune system, a process known as “immunogenic cell death” (ICD) (https://pubmed.ncbi.nlm.nih.gov/27748397/). A recent study, led by Ken Anderson from Dana-Farber Cancer Institute, reports a novel mechanism by which the proteasome inhibitor bortezomib, one of the most effective anti-myeloma agents, induces cell death in myeloma cells that relies on the induction of antitumor immune responses (https://bloodcancerdiscov.aacrjournals.org/content/early/2021/06/03/2643-3230.BCD-21-0047.1) 

This is particularly important in multiple myeloma (MM), a highly heterogeneous disease that resides in a complex ecosystem comprising of immune, endothelial, and stromal cells. The introduction of agents targeting MM cells in their microenvironment, such as immunomodulatory drugs, has markedly improved the survival of MM patients. In MM, however, the efficacy of immune-based approaches is hampered by intrinsic resistance of malignant plasma cells to activated immune-effectors, and by the immunosuppressive bone marrow milieu. Restoration of anti-tumor immunity primed by immunogenic cancer cells may be exploited to convert the immunologically “cold” MM into a “hot” MM and may lead to long-term clinical benefit, even in high-risk cytogenetic patient subgroups.   

 In this study, Gulla’ and colleagues show that ICD and viral mimicry via the activation of the STING pathway is an important feature contributing to the therapeutic efficacy of bortezomib in MM, corroborating past studies (https://pubmed.ncbi.nlm.nih.gov/17299090/). “The validation of bortezomib as an immunogenic drug and the identification of STING as a novel therapeutic target in MM enhances our understanding of ICD mechanisms in MM and has important clinical implications for the treatment of our patients” first author Annamaria Gulla’ said. “ICD induced by bortezomib may underlie the enhanced clinical activity when combined with immunomodulatory drugs and/or monoclonal antibodies and suggest its future utility in combination immunotherapeutic approaches in MM”, added lead author Kenneth Anderson.  

 “With the emerging integration of immune therapies such as bispecifics and CART cells into frontline therapy for MM, understanding immunogenic effects of current therapies will be particularly relevant for developing optimal combinations” commented the expert in myeloma immunobiology Dr Madhav Dhodapkar, from Emory University School of Medicine.  

 Recognition of its immune effect as a potent ICD inducer will therefore inform the broader use of bortezomib, and perhaps other ICD inducers, in combination with immunotherapies, including STING agonists, to improve the clinical management and patient outcome in MM.