BACKGROUNDThis open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma. METHODSWe randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival. RESULTSThe median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P<0.001; and 4-year overall survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P = 0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P = 0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively). CONCLUSIONSConsolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with MPR, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00551928. 896T h e ne w e ngl a nd jou r na l o f m e dicine H igh-dose chemotherapy plus autologous stem-cell transplantation, as compared with conventional chemotherapy, prolongs progression-free survival and overall survival among patients with newly diagnosed multiple myeloma.1-4 and it is currently the standard of care for patients who are younger than 65 years of age. However, since autologous stem-cell transplantation has substantial toxic effects and requires prolonged hospitalization, the comparison with less toxic, orally administered treatments is important. Immunomodulatory drugs and proteasome inhibitors have significantly improved outcomes in patients, regardless of whether they are eligible for transplantation. 5-18These improvements have raised questions about the role of transplantation in comparis...

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IntroductionNatural killer (NK) cells are cytotoxic and cytokine-producing lymphocytes, involved in the immune defense against viral infections and tumors. 1 Their homeostasis is regulated by cytokines and membrane associate receptors able to inhibit or activate cellular programs. 2 The inhibitory receptors are well characterized and described extensively in several reviews. [3][4][5] Triggering of NK cells depends largely on NK receptor member D of the lectinlike receptor family (NKG2D) and natural cytotoxicity receptors (NCRs): NKp46, NKp44, NKp30. 6,7 NCRs are involved in the recognition of several tumor cell lines, although their ligands remain elusive. 6 NKG2D recognizes the MHC (major histocompatibility complex) class I chain-related (MIC) protein A (MICA) and B (MICB); both are nonclassic class I molecules. The UL16-binding proteins (ULBP1-3 or RAET1 proteins; ULBP1-3 in this paper) are the second group of NKG2D ligands in humans. MICs are expressed during virus infection or cell transformation; ULBP expression in fresh tumor cells is essentially unknown; only long-term cultured in vitro cell lines have been looked at so far. [8][9][10] Cytotoxic T lymphocytes (CTLs) and interferons (IFNs) have a key role in tumor progression and tumor "immune-editing process." 11 MHC class I molecule loss is a frequent event in tumor progression and could prevent CTL recognition. However, theoretically, NK cells could recognize MHC class I-defective tumors, according with the "missing self hypothesis." 12 So far, only in mouse models NK cells were demonstrated to destroy in vivo lymphoma and melanoma tumors with reduced MHC class I expression and/or with high levels of activating target structures. [13][14][15] Even though almost 30 years ago human NK cells were discovered for their in vitro antitumor cytotoxicity, we still have little information concerning the regulation of their antitumor activity in vivo or ex vivo. 16,17 Therefore, several questions remain to be addressed to understand the antineoplastic potential of human NK lymphocytes:1. HLA class I molecules are reported to be down-regulated during solid tumor progression. 18 19,20 Other hematopoietic-derived cells can stimulate NK lymphocytes as described for dendritic cells (DCs). 21 The B-cell membrane-associated proteins CD40 and CD1 regulate natural killer cell cytotoxicity. [22][23][24][25] Furthermore, NK lymphocytes are specifically activated after bone marrow graft but not by other tissue transplantations. 26 They localize in lymph nodes and spleen, mainly in B-cell follicles and in the marginal zone. 27 Blood, spleen, and bone marrow are the anatomic districts where the highest number and activity of NK cells are present. 1 Taking together these considerations, hematologic malignancies (B-cell-derived tumors in particular) could be considered an appealing system to investigate the potential role of NK cells in the control of tumor progression.Multiple myeloma (MM) is a plasma cell-derived tumor. It is characterized by accumulation of plasma cells in th...

AperTO -Archivio Istituzionale Open Access dell'Università di TorinoChemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: A randomised, multicentre, phase 3 trial / Gay, Francesca; Oliva, Stefania; Petrucci, Maria Teresa; Conticello, Concetta; Catalano, Lucio; Corradini, Paolo; Siniscalchi, Agostina; Magarotto, Valeria; Pour, Ludk; Carella, Angelo; Malfitano, Alessandra; Petrò, Daniela; Evangelista, Andrea; Spada, Stefano; Pescosta, Norbert; Omedè, Paola; Campbell, Philip; Liberati, Anna Marina; Offidani, Massimo; Ria, Roberto; Pulini, Stefano; Patriarca, Francesca; Hajek, Roman; Spencer, Andrew; Boccadoro, Mario; Palumbo, Antonio. -In: LANCET ONCOLOGY. -ISSN 1470-ISSN -2045-ISSN . -16:16(2015, pp. 1617-1629. Original Citation:Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: A randomised, multicentre, phase 3 trial This is an author version of the contribution published on:Questa è la versione dell'autore dell'opera: [Lancet Oncol. 2015 Dec;16(16):1617-29. doi: 10.1016/S1470-2045 Background. High-dose melphalan plus autologous stem-cell transplantation (MEL200-

In comparison with a single ASCT as up-front therapy for newly diagnosed MM, double ASCT effected superior CR or nCR rate, RFS, and EFS, but failed to significantly prolong overall survival. Benefits offered by double ASCT were particularly evident among patients who failed at least nCR after one autotransplantation.