The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).

BACKGROUNDLenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population. METHODSWe randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival. RESULTSAt a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 10 5 white cells) (P<0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumumab group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%). CONCLUSIONSAmong patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.

No abstract

Matrix metalloprotease type 9 (MMP-9) has been functionally implicated in VEGF activation, the induction and maintenance of chronic angiogenesis, and early stage tumor growth in a number of mouse models of cancer. In this article, we have identified two inflammatory cell types that are major sources of MMP-9 in the angiogenic stages of pancreatic islet carcinogenesis that unfold in RIP1-Tag2 transgenic mice. MMP-9-expressing neutrophils were predominantly found inside angiogenic islet dysplasias and tumors, whereas MMP-9-expressing macrophages were localized along the periphery of such lesions. Transient depletion of neutrophils significantly suppressed VEGF:VEGF-receptor association, a signature of MMP-9 activity, and markedly reduced the frequency of initial angiogenic switching in dysplasias. Thus infiltrating neutrophils can play a crucial role in activating angiogenesis in a previously quiescent tissue vasculature during the early stages of carcinogenesis.VEGF ͉ macrophage ͉ granulocyte colony-stimulating factor (G-CSF) ͉ angiogenesis ͉ matrix metalloprotease type 9 T umors and their neoplastic progenitors are composed not only of transformed ''cancer cells'' but also of other cell types constituting the stroma. These stromal cells include cancerassociated fibroblasts, endothelial cells, pericytes, and a variable representation of leukocytes, including macrophages, neutrophils, mast cells, and B or T lymphocytes (1, 2). Increasing evidence indicates that leukocytic infiltration can either antagonize tumor formation and growth (immune surveillance) (2, 3) or, alternatively, promote tumor phenotypes, such as angiogenesis, growth, and invasion (immune enhancement) (1, 4, 5). Historically, tumor-infiltrating leukocytes have been considered to be manifestations of an intrinsic defense mechanism against developing tumors (2). However, most solid tumors are largely recognized as self and do not evoke effective immune responses capable of killing or antagonizing tumor formation, growth, and progression (3, 6). In contrast, accumulating clinical data for solid tumors show a correlation between high-density leukocytic infiltration into tumors and poor outcome of patients (1). In regard to the innate immune system, despite its capability to stimulate acquired immune responses, the weight of the evidence indicates that infiltration by innate immune cell types is tumorpromoting in many organs and tumorigenesis pathways (1,7,8). In addition to protumorigenic activities of tumor associated macrophages (9-11), neutrophils also have been shown to enhance the in vitro invasive and in vivo metastatic potential of syngeneic tumor cells by facilitating invasion into basement membrane (7).Genetically engineered mouse models of cancer are proving instructive about the immunobiology of tumors, revealing both enhancing and antagonizing roles played by the adaptive and innate immune system (4,5,(12)(13)(14). RIP1-Tag2 transgenic mice constitute a well characterized prototypical model for multistep carcinogenesis, involving the pancr...