Immunotherapy of multiple myeloma

Abstract

had markedly impaired IFN-γ production, although this phenotype was reversible (13). Together, these studies indicate that T cell-dependent myeloma immunity is present, albeit suppressed, in patients with myeloma.NK cells play a key role in myeloma immunity, and NK dysfunction has been implicated in myeloma progression in nontransplanted myeloma-bearing mice (42). MGUS patients were found to have similar or increased numbers of NK cells compared with healthy donors, while patients with late-stage myeloma have significantly reduced NK cell numbers (43, 44). NK cells are particularly important in the context of treatment with immunomodulatory imide drugs (IMiDs), as IMiDs stimulate IL-2 production by T cells, resulting in NK cell activation and expansion (40,45,46). Furthermore, a recent study found that IMiDs prime myeloma for killing by daratumumab, a CD38-targeting mAb, by upregulating CD38 expression and sensitizing myeloma cells to NK cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) (47). A second antibody, elotuzumab, binds SLAMF7 on MM cells and Fc receptors (CD16) on NK cells and macrophages to promote ADCC and antibody-dependent cellular phagocytosis (48). This mAb does not have single-agent activity but is active in combination with IMiDs. NK cell-mediated myeloma immunity was addressed in a murine model of ASCT, and surprisingly, NK cells were not required for myeloma control in this setting (26). These data suggest that alternative mechanisms may underpin responses after ASCT, although this has yet to be definitively investigated in a clinical setting.

KRAS, NRAS, and BRAF mutations in plasma cell myeloma at a single Korean institute

“…A recent study suggested that the development of mutation-specific KRAS inhibitors could be of great value in patients with KRAS -mutant PCM [ 32 , 33 ]. Moreover, results of the correlation between RAS/RAF mutations and complex karyotypes suggested the therapeutic benefit of checkpoint inhibitors in this group [ 34 ].…”

Harnessing the Immune System Against Multiple Myeloma: Challenges and Opportunities

“…In this phase, resistant tumor cells acquire genetic and epigenetic alterations that eventually lead to escape the immune recognition, allowing for uncontrolled proliferation and clinical progression (escape) ( 19 – 21 ). A potential application of this model in MM identifies in the MGUS/SMM precursor stages a phase of immune equilibrium ( 22 ). In this context, marked heterogeneity of MM cells, along with constitutive and ongoing genomic instability, and modulations occurring in the composition of the BM milieu may underlie immune escape and disruption of the immune equilibrium during disease progression ( 22 ).…”

“…A potential application of this model in MM identifies in the MGUS/SMM precursor stages a phase of immune equilibrium ( 22 ). In this context, marked heterogeneity of MM cells, along with constitutive and ongoing genomic instability, and modulations occurring in the composition of the BM milieu may underlie immune escape and disruption of the immune equilibrium during disease progression ( 22 ). Specifically, the strict and symbiotic interaction between MM cells and the BM microenvironment facilitate tumor immune escape via several mechanisms: immunosuppressive cells in the BM; disruption of antigen presentation by downregulating major histocompatibility complex and/or costimulatory molecules; loss or mutation of cancer-specific antigens; and upregulation of decoy receptors or complement inhibitory receptors ( 5 , 23 ).…”

Drug Conjugated and Bispecific Antibodies for Multiple Myeloma: Improving Immunotherapies off the Shelf

“…Immune dysregulation retains a crucial role in the pathogenesis and disease progression of multiple myeloma (MM), since genetic lesions per se are necessary but not sufficient to the progression from monoclonal gammopathy of undetermined significance (MGUS) to overt MM [ 1 , 2 ]. Several factors including T cell exhaustion, tolerance induction by tumor associated microenvironment, cytokines production alteration and increase in myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages with suppressive properties contribute in the neoplastic escape form immune surveillance, ultimately leading to disease progression [ 3 , 4 , 5 , 6 ]. Allogenic stem cell transplantation is traditionally regarded as the first immunotherapeutic strategy and the only curative option for many hematological malignancies.…”