Abstract
The incidence of multiple myeloma (MM), a bone marrow (BM) resident hematological malignancy, is increasing globally. The disease has substantial morbidity and mortality and remains largely incurable. Clinical studies show that autologous stem cell transplantation (ASCT) remains efficacious in eligible patients, providing a progression free survival (PFS) benefit beyond novel therapies alone. Conventionally, improved PFS after ASCT is attributed to cytoreduction from myeloablative chemotherapy. However, ASCT results in immune effects beyond cytoreduction, including inflammation, lymphodepletion, T cell priming via immunogenic cell death, and disruption of the tumor BM microenvironment. In fact, a small subset of patients achieve very long-term control of disease post-ASCT, akin to that seen in the context of immune-mediated graft-vs.-myeloma effects after allogeneic SCT. These clinical observations coupled with recent definitive studies in mice demonstrating that progression after ASCT represents immune escape as a consequence of T cell exhaustion, highlight the potential for new immunotherapy maintenance strategies to prevent myeloma progression following consolidation with ASCT.
Highlights
Autologous stem cell transplantation (ASCT) occurs after treatment with varying combinations of proteasome inhibitors, alkylating agents, immunomodulatory drugs (IMiDs), steroids and most recently, monoclonal antibodies until a maximal response is achieved
IL-6 inhibition is capable of impacting myeloma growth in vitro and in preclinical models, it has been largely unsuccessful in the clinical setting; which may be unsurprising given the immune-suppressive nature of an established tumor microenvironment (TME) in refractory multiple myeloma (RRMM)
We demonstrated that IL-17A, a highly microbiota-dependent cytokine [61], is pathogenic after ASCT and acts directly on myeloma cells in the bone marrow (BM) to promote relapse [17]
Summary
Autologous stem cell transplantation (ASCT) occurs after treatment with varying combinations of proteasome inhibitors, alkylating agents, immunomodulatory drugs (IMiDs), steroids and most recently, monoclonal antibodies until a maximal response is achieved. Patients receive myeloablative chemotherapy, predominantly highdose melphalan [1], followed by autologous stem cell rescue and subsequent maintenance therapy with an IMID, typically lenalidomide. This regimen remains a highly effective therapy and, despite recent advances in anti-myeloma therapeutics, ASCT provides a progression-free survival benefit beyond novel agents alone [2,3,4,5]. There are several key immunological changes that occur after ASCT that strongly suggest that long-term myeloma control after transplant is due to more than just cytoreduction In this perspective, we will outline key evidence from both clinical. ASCT Is Immunotherapy for Myeloma observations and definitive preclinical studies that support the concept that ASCT sets the stage for myeloma-specific immunity
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