Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumor genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the dataset. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signaling was suggested by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.

SUMMARY We performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations, and discovered putative tumor suppressor genes by determining homozygous deletions and loss-of-heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53 and DIS3 (particularly in non-hyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g. KRAS, NRAS and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of non-mutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions.

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Carfilzomib is a next-generation

We have studied a three drug combination with bortezomib, cyclophosphamide and dexamethasone (CyBorD) on a 28 day cycle in the treatment of newly diagnosed multiple myeloma patients to assess response and toxicity. The primary endpoint of response was evaluated after four cycles. Thirty-three newly diagnosed, symptomatic patients with multiple myeloma received bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, 11, cyclophosphamide 300 mg/m2 orally days 1, 8, 15, 22 and dexamethasone 40 mg orally days 1-4, 9-12, 17-20 on a 28 day cycle for four cycles. Responses were rapid with a mean 80% decline in the sentinel monoclonal protein at the end of two cycles. The overall intent to treat response rate (≥ partial response) was 88% with 61% ≥VGPR and 39% CR/nCR. For the 28 patients that completed all 4 cycles of therapy the CR/nCR rate was 46% and ≥VGPR rate 71%. All patients undergoing stem cell harvest had a successful collection. Twenty three patients underwent SCT and are evaluable through day 100 with CR/nCR documented in 70% and ≥VGPR in 74%. In conclusion, CyBorD produces a rapid and profound response in patients with newly diagnosed multiple myeloma with manageable toxicity.

Background: B-cell maturation antigen (BCMA) is a tumour necrosis superfamily cell-surface receptor required for plasma cell survival. This study evaluated safety, tolerability and preliminary clinical activity of GSK2857916, a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin-F, in patients with relapsed/refractory multiple myeloma (MM). Methods: This international, multicentre, open-label, first-in-human Phase 1 study comprised dose escalation (Part 1) and dose expansion (Part 2) phases. Adults with histologically or cytologically confirmed MM, Eastern Cooperative Oncology Group performance status 0/1, and progressive disease following stem cell transplant, alkylators, proteasome inhibitors and immunomodulators were recruited. In Part 1, patients received GSK2857916 (0 03–4 6 mg/kg) via 1-hour intravenous infusion. In Part 2, patients received the selected dose of GSK2857916 (3 4 mg/kg) every 3 weeks. Primary endpoints were maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). All patients who received ≥1 dose were included in this prespecified administrative interim analysis (cut-off: 26 June 2017), which was performed for internal purposes. The study is ongoing (NCT02064387). Findings: Between July 2014 and February 2017, 73 patients were treated (Part 1 n=38; Part 2 n=35). No MTD was identified in Part 1. Based on safety/clinical activity, 3 4 mg/kg was selected as RP2D. Corneal events were common (42/73; 58%); most (37/42) were Grade 1/2 and did not result in treatment discontinuation in Part 2. The other most common Grade 3/4 events were thrombocytopenia (25/73; 34%) and anaemia (11/73; 15%). There were 12 treatmentrelated serious adverse events and no treatment-related deaths. Overall response rate at 3 4 mg/kg in Part 2 was 60% (21/35; 95% confidence interval: 42 1%–76 1%). Interpretation: At the identified RP2D, GSK2857916 is well tolerated and data suggest it has good clinical activity in heavily pretreated patients, thereby indicating that this may be a promising candidate for the treatment of relapsed/refractory MM. Funding: GlaxoSmithKline plc

Purpose: The ubiquitously expressed transmembrane glycoprotein CD47 delivers an anti-phagocytic (do not eat) signal by binding signal-regulatory protein a (SIRPa) on macrophages. CD47 is overexpressed in cancer cells and its expression is associated with poor clinical outcomes. TTI-621 (SIRPaFc) is a fully human recombinant fusion protein that blocks the CD47-SIRPa axis by binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of this inhibitory axis using TTI-621 has emerged as a promising therapeutic strategy to promote tumor cell eradication.Experimental Design: The ability of TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. In vivo antitumor efficacy was evaluated in xenograft and syngeneic models and the role of the Fc region in antitumor activity was evaluated using SIRPaFc constructs with different Fc tails.Results: TTI-621 enhanced macrophage-mediated phagocytosis of both hematologic and solid tumor cells, while sparing normal cells. In vivo, TTI-621 effectively controlled the growth of aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail of TTI-621 plays a critical role in its antitumor activity, presumably by engaging activating Fcg receptors on macrophages. Finally, TTI-621 exhibits minimal binding to human erythrocytes, thereby differentiating it from CD47 blocking antibodies.Conclusions: These data indicate that TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications.

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