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In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progressionfree survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-totreat analysis; VTD, n ‫؍‬ 236; TD, n ‫؍‬ 238). This per-protocol analysis (VTD, n ‫؍‬ 160; TD, n ‫؍‬ 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTDtreated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the

IntroductionOver the last decade, major advances in the treatment of multiple myeloma (MM) have been reported with the use of autologous stem-cell transplantation [1][2][3][4] and, more recently, of novel agents targeting the tumor clone and the bone marrow microenvironment. 5 In this setting, thalidomide represents a new treatment paradigm because of its alternative mechanisms of action that include disruption of myeloma-bone marrow stromal cell interactions, inhibition of cytokine secretion, and immunomodulatory effects. The observation that increased bone marrow angiogenesis correlates with advanced phases of MM, 6 along with the welldocumented in vitro antiangiogenic activity of thalidomide, 7 led to the investigational use of this agent in patients with advanced and refractory MM. 8 Response rates in the 30% range initially reported by Singhal et al 8 were extended and confirmed by other groups (for a review, see Cavenagh and Oakervee 9 and Dimopoulos et al 10 ). Subsequent combination of thalidomide with dexamethasone increased the rate of response up to 50% to 55%, 11,12 suggesting a synergism between these agents and providing the rationale for their use as primary therapy for patients with symptomatic MM. Results of 3 phase-2 studies with thalidomide-dexamethasone (Thal-Dex) in preparation for subsequent autologous transplantation 13-15 and a randomized comparison of Thal-Dex with dexamethasone alone 16 were promising in terms of response rate and collection of adequate quantities of peripheral blood stem cells (PBSCs). Based on these data, Thal-Dex has been proposed, and is currently accepted at many centers, as a front-line treatment option for patients with symptomatic MM, particularly if it is planned to offer subsequent high-dose therapy with autologous transplantation. However, no comparative study of Thal-Dex with vincristinedoxorubicin-dexamethasone (VAD), the reference treatment used so far to reduce tumor cell mass before autologous transplantation, has been reported. To address this issue, we performed a retrospective matched case-control analysis of 200 patients with symptomatic MM who were primarily treated with Thal-Dex (n ϭ 100) or VAD (n ϭ 100) in preparation for autologous stem-cell transplantation as part of 2 consecutive studies conducted from 1996 to 2004. Table 1; the 2 groups were comparable with respect to the major presenting variables known to potentially affect clinical outcome. Both studies were approved by local ethical committees of participating centers. Informed consent was provided according to the Declaration of Helsinki. Patients, materials, and methods Patients and criteria of matching Study design and treatment regimensBy design of both studies, Thal-Dex and VAD were planned to be administered for 4 months in an attempt to reduce tumor cell mass before collection of PBSCs and subsequent autologous transplantation. Details on treatment regimens were given elsewhere. 4,15 Briefly, thalidomide was given orally at the starting dose of 100 mg/d for 14 days and then increa...

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In this study, we demonstrate expression and examined the biologic sequelae of PI3K/p110␦ signaling in multiple myeloma ( IntroductionThe bone marrow (BM) microenvironment plays a crucial role in pathogenesis of multiple myeloma (MM) by promoting cell proliferation, survival, migration, and drug resistance. [1][2][3][4] The PI3K/AKT pathway mediates growth and drug resistance in MM cells and also plays a significant role in autophagy. 5,6 PI3K is activated via upstream tyrosine kinase-associated receptors for growth factors, cytokines, antigens, and costimulatory molecules. It in turn activates AKT, which mediates cell proliferation, cell cycle, apoptosis, and autophagy. 7 Class IA PI3K consists of 5 isoforms of regulatory subunits (p85␣, p50␣, p55␣, p85␤, and p55␥), which interact with class IA isoforms. Class IA PI3K is composed of p110␣, -␤, and -␦ isoforms. 8 Among the 8 distinct mammalian isoforms of PI3K, class I PI3Ks are responsible for Akt activation. Importantly, p110␦ is expressed in many cancers, including colon and bladder carcinoma, glioblastoma, and acute myeloid leukemia blasts. 9,10 In the current study, we demonstrate high expression of p110␦ in patient MM cells. Previous studies have shown that CAL-101, a potent and selective p110␦ inhibitor, has broad antitumor activity against cancer cells of hematologic origin. 11,12 Moreover, inhibition of p110␦ induces cleavage of caspases and LC3, consistent with apoptotic and autophagic cell death, respectively. Here we show that p110␦ blockade with CAL-101, a potent and selective p110␦ inhibitor, inhibits MM cell growth even in the presence of interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), or bone marrow stromal cells (BMSCs), associated with decreased phosphorylation of AKT and P70S6k. We also confirmed inhibition of human MM cell growth triggered by p110␦ inhibition in our xenograft mouse models of human MM. These studies therefore show that small molecule inhibitors of p110␦ trigger significant anti-MM cytotoxicity both in vitro and in vivo, providing the framework for their clinical evaluation to improve patient outcome in MM. Methods Materialsp110␦ inhibitor CAL-101 and IC488743 were provided by Calistoga Pharmaceuticals. CAL-101 was dissolved in dimethyl sulphoxide at 10mM and stored at Ϫ20°C for in vitro study. IC488743 was dissolved in 1% carboxyl methylcellulose/0.5% Tween 80 and stored at 4°C for in vivo study. Recombinant human p110␣, ␤, ␥, and ␦ were reconstituted with sterile phosphate-buffered saline (PBS) containing 0.1% bovine serum albumin. Bortezomib was provided by Millennium Pharmaceuticals. 3-Methyladenine was purchased from Sigma-Aldrich. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. Cell culture Dex 1460BLOOD, 2 SEPTEMBER 2010 ⅐ VOLUME 116, NUMBER 9For personal use only. on March 28, 2019. by guest www.bloodjournal.org From Germany). LB human MM ce...