12/6/2023 0 Comments Autologous stem cell transplantT cell reconstitution occurs more slowly after ASCT and can take up to a year to return to pre-transplant numbers ( 10). Whether this holds true in patients after ASCT, particularly in those receiving maintenance therapies with IMIDs requires further investigation. Therefore, although NK cells are potent mediators of myeloma immunity, they may not be critical when a robust T cell response is generated post-ASCT. However, NK cell-mediated myeloma immunity was found to be dispensable for myeloma control after ASCT in a murine model when donor T cells were transplanted ( 17). NK cells have been shown to be especially important in the context of IMiDs such as thalidomide, lenalidomide, and pomalidomide, since these agents stimulate IL-2 production that promotes NK cell expansion and activation ( 14– 16). Importantly, NK cell dysfunction has been associated with myeloma progression in non-transplant murine models and patients with late-stage myeloma have reduced NK cell numbers suggesting that these cells may play an important role in myeloma control ( 11– 13). Natural killer (NK) cells usually reconstitute to normal levels within 1 month of ASCT much faster than adaptive immune cells such as B and T cells ( 9, 10). Immune Reconstitution and Myeloma-Specific T Cells In this perspective, we will outline key evidence from both clinical observations and definitive preclinical studies that support the concept that ASCT sets the stage for myeloma-specific immunity. In fact, 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. However, there is a subset of patients that enter a plateau-phase of disease control after achieving a complete response to ASCT, akin to immune-mediated graft-vs.-leukemia effects after allogeneic-SCT ( 7, 8). Hitherto, the control of myeloma progression induced by ASCT is largely attributed to the direct cytoreductive effects of myeloablative chemotherapy on myeloma cells ( 6). 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– 5). ![]() Patients then receive myeloablative chemotherapy, predominantly high-dose melphalan ( 1), followed by autologous stem cell rescue and subsequent maintenance therapy with an IMID, typically lenalidomide. At that point, eligible patients typically undergo G-CSF-based stem cell mobilization followed by autologous stem cell collection and storage. ![]() 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.Īutologous 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. 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. ![]() ![]() 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. Conventionally, improved PFS after ASCT is attributed to cytoreduction from myeloablative chemotherapy. 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. The disease has substantial morbidity and mortality and remains largely incurable. The incidence of multiple myeloma (MM), a bone marrow (BM) resident hematological malignancy, is increasing globally.
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