The cellular inhibitor of apoptosis cIAP1 and −2 are amplified in about 3% of cancers, and were identified in multiple malignancies as potential therapeutic targets due to their role in evasion of apoptosis. Consequently, small molecule IAP antagonists, like LCL161, have entered clinical trials for their ability to induce TNF-mediated apoptosis of cancer cells. However, cIAP1 and −2 are recurrently homozygously deleted in multiple myeloma resulting in constitutive activation of the non-canonical NFkB pathway. It was therefore counterintuitive to observe a robust in vivo anti-myeloma activity of LCL161 in a transgenic myeloma mouse model and patients with relapsed-refractory myeloma, where addition of cyclophosphamide resulted in a median progression free survival of 10 months. This effect is not due to direct induction of tumor cell death, but rather to upregulation of a tumor cell autonomous type I interferon signaling and a strong inflammatory response with activation of macrophages and dendritic cells resulting in phagocytosis of tumor cells. Treatment with LCL161 established long-term anti-tumor protection and cure in a fraction of transgenic Vk*MYC mice. Remarkably, combination of LCL161 with the immune-checkpoint inhibitor anti-PD1 was curative in all treated mice.

The gut microbiota has been causally linked to cancer, yet how intestinal microbes influence progression of extramucosal tumors is poorly understood. Here we provide evidence implying that Prevotella heparinolytica promotes the differentiation of Th17 cells colonizing the gut and migrating to the bone marrow (BM) of transgenic Vk*MYC mice, where they favor progression of multiple myeloma (MM). Lack of IL-17 in Vk*MYC mice, or disturbance of their microbiome delayed MM appearance. Similarly, in smoldering MM patients, higher levels of BM IL-17 predicted faster disease progression. IL-17 induced STAT3 phosphorylation in murine plasma cells, and activated eosinophils. Treatment of Vk*MYC mice with antibodies blocking IL-17, IL-17RA, and IL-5 reduced BM accumulation of Th17 cells and eosinophils and delayed disease progression. Thus, in Vk*MYC mice, commensal bacteria appear to unleash a paracrine signaling network between adaptive and innate immunity that accelerates progression to MM, and can be targeted by already available therapies.

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Although chemotherapeutic agents and molecular medicine are pillars of successful treatment of cancer, the recent clinical development of immunotherapies shows compelling promise in the treatment of many tumor types. In hematologic malignancies, immunotherapies centered upon cytolytic T lymphocytes as drugs, such as chimeric antigen receptor (CAR)-T cells and bispecific T-cell engagers (BiTE) or antibodies (BsAb), are central among these advances. BiTEs and BsAbs are "offthe-shelf" drug therapies that circumvent the need for timeconsuming and expensive ex vivo manipulation of patient cells. These agents often consist of monoclonal antibodies or singlechain variable fragments in the case of BiTEs, engineered with one binding site directed toward a tumor-specific antigen and another against the T-lymphocyte activating receptor CD3epsilon. BsAbs redirect T cells to kill tumors by bringing them into physical contact and activating secretion of cytotoxic molecules (1). Due to their novel mode of action, BsAb therapeutics may provide an effective option for all patients, including those with cytogenetically high-risk or heavily pretreated disease that renders them more resistant to standard-of-care therapy.

The most common genetic abnormality in multiple myeloma is the deletion of chromosome 13, seen in almost half of newly diagnosed patients. Unlike chronic lymphocytic leukemia, where a recurrent minimally deleted region including MIR15A/MIR16-1 has been mapped, the deletions in multiple myeloma predominantly involve the entire chromosome and no specifi c driver gene has been identifi ed. Additional candidate loci include RB1 and DIS3 , but while biallelic deletion of RB1 is associated with disease progression, DIS3 is a common essential gene and complete inactivation is not observed. The Vk*MYC transgenic mouse model of multiple myeloma spontaneously acquires del(14), syntenic to human chromosome 13, and Rb1 complete inactivation, but not Dis3 mutations. Taking advantage of this model, we explored the role in multiple myeloma initiation and progression of two candidate loci on chromosome 13: RB1 and MIR15A/MIR16-1. Monoallelic deletion of Mir15a/Mir16-1, but not Rb1, was suffi cient to accelerate the development of monoclonal gammopathy in wild-type mice and the progression of multiple myeloma in Vk*MYC mice, resulting in increased expression of Mir15a/Mir16-1 target genes and plasma cell proliferation, which was similarly observed in patients with multiple myeloma. SIGNIFICANCE: In the absence of a defi ned, minimally deleted region the signifi cance of del(13) in multiple myeloma has remained controversial. Here we show that haploinsuffi ciency of Mir15a/Mir16-1 , but not Rb1 , upregulates the cell cycle-regulatory network, inducing monoclonal gammopathy in mice and promoting multiple myeloma progression in both mice and men.