Efficacy of new drugs as induction treatment before single or tandem autologous stem cell transplantation in newly diagnosed multiple myeloma patients: a single centre experience

The outcome of patients affected by Multiple Myeloma (MM) has markedly improved over the past decade, both in young and elderly patients. In the past years, conventional therapy, such as melphalan plus prednisone (MP), was the only active treatment against MM. Since the 1980s, high doses of chemotherapy plus autologous stem cell transplantation (ASCT) proved to be the most suitable option for young newly diagnosed multiple myeloma (YNDMM) patients. More recently, new active classes of drugs, such as proteasome inhibitors-PIs (e.g., bortezomib) and immunomodulatory drugs-IMiDs (e.g., thalidomide and lenalidomide) became the standard of care, alone or in association with the old agents, either for fırst-line therapy in the transplant and non-transplant settings, or for the treatment of relapsed disease. Actually, three-drugs combinations, including at least bortezomib or lenalidomide in combination with dexamethasone, followed by ASCT is considered the optimal choice for all YNDMM. Patients and Methods: we retrospectively analyzed our Centre experience in the last 25 years comparing the results obtained with old drugs- that is conventional chemotherapy- versus novel agents –such as lenalidomide and bortezomib- in YNDMM. We also performed an additional analysis on the effect of a single versus tandem ASCT either with old agents or with novel agents. Results: Between August 1989 and May 2014, 258 YNDMM patients underwent ASCT. The median age was 54 years (range, 18-69), 137 were men. As induction treatment, between October 1988 and October 2008, 173/258 patients received old drugs, i.e. vincristine, doxorubicin and dexamethasone (VAD; n=167) or MP (n=6), while 85/258 patients, between February 2005 and November 2013, were treated with novel agents, i.e. velcade-based (n=67) or IMiD-based regimens (n=18). All 258 patients received high doses of melphalan and single (n=153) or tandem (n=105) ASCT. Overall, after induction, 67 patients (25.9%) achieved complete response (CR), near CR (nCR) or very good partial response (VGPR). More in detail, among patients treated with new drugs, a CR/nCR/VGPR was observed in 36/85 patients (42.3%) after induction, in 36/85 patients (42.3%) after single ASCT and in 27/50 patients (54%) after tandem ASCT. No differences were observed in terms of response and survival between IMiDs or bortezomib-based regimens. For patients treated with old drugs, a CR/nCR/VGPR was recorded in 31/173 (17.9%) after induction, in 50/173 patients (28.9%) after single ASCT and in 19/55 patients (34.5%) after tandem ASCT. Overall survival (OS) and progression-free survival (PFS) at 10 years, for all 258 patients, was 44.4% and 22.5%, respectively. OS and PFS were better for patients in CR/nCR/VGPR after induction compared to those in partial response or stable disease (OS: 62.1% vs 40.7%, p=0.06 and PFS: 36.2% vs 17.2%, p=0.06). In addition, OS was slightly better for patients treated with new drugs than those treated with old drugs. In fact, OS at 8 years was 66.1% (IC 95%:53.5-81.7) for the first group vs 51.5% for the second group, respectively (p = 0.26 n.s.). PFS was significantly improved for patients treated with new drugs than those treated with old drugs. In fact, PFS at 8 years was 55% for the first group vs 25.3% for the second group, respectively (p = 0.0047). Supposing that the impact on OS was influenced by the salvage treatments used after the progression of disease, we further analyzed patients that relapsed. Among our 258 patients, 144 presented a first relapse. Our cohort of relapsed patients was divided in 4 different groups: 1) 51 patients treated with old agents as first and second line therapy (35.4%); 2) 79 patients treated with old agents for first line therapy and novel agents for second line therapy (54.8%); 3) 2 patients treated with novel agents in induction therapy and subsequent old agents in second line therapy for worsening clinical condition (1.4%); 4) 12 patients treated with novel agents both in first and second line treatment (8.3%). Our analysis was focused on group 1 and 2. The group 3 was not considered for the small number of patients and because the choice of treatment was based exclusive on clinical worsening condition; the group 4 was not included for the small number of patients and because follow up is too short. OS at 10 years for patients of group 2 was significantly higher than patients of group 1 (20.4 vs 2.4%; p < 0.0001). Also PFS at 10 years showed better results for patients of group 2 (10% vs 2.3%; p = 0.02). The PFS2 at 10 years, considered as the interval from the start of the first line treatment to progression after second-line therapy or death from any cause, showed better results for patients of group 2 than patients of group 1 (25.7% vs 9.2%; p = 0.0002). Conclusions: Our experience confirmed that novel agents provide better outcome and deeper responses as induction treatment for YNDMM patients and tandem ASCT still improve the responses in these patients. Moreover, novel agents have also a significant impact in the subsequent lines of treatments, showing better results in terms of PFS2. In the light of the newer IMiDs and PIs, the challenge is to assess the exact role of ASCT in the modern setting; our next effort will be the evaluation of YNDMM patients treated with the new-generation agents (carfilzomib and others) in terms of outcome and safety, and the role of ASCT even in this setting, in a larger cohort of patients and with a appropriate follow up

Detection of influenza A(H1N1)pdm09 virus in a patient travelling from Shanghai to Italy in July 2018: an uncommon clinical presentation in a non-seasonal period

Influenza is one of the most common infectious diseases in travellers, especially in those returning from subtropical and tropical regions.In late June 2018 an influenza A(H1N1)pdm09 virus infection was diagnosed in a 36-years-old man, returned from a travel in Shanghai and hospitalized at the Ospedale Policlinico San Martino, Genoa, Italy, with a diagnosis of fever and an uncommon clinical presentation characterised by a persistent leukopenia. Phylogenetic analysis revealed a closeness with influenza A(H1N1)pdm09 strains circulating in the US in May-June 2018.Prompt recognition of influenza infection led to a proper case management, demonstrating the crucial role of the continuous influenza surveillance programme

Carfilzomib, lenalidomide, and dexamethasone in relapsed refractory multiple myeloma: a prospective real-life experience of the Regional Tuscan Myeloma Network

IntroductionCarfilzomib, a potent, irreversible, selective proteasome inhibitor has demonstrated consistent results in relapsed/refractory multiple myeloma (RRMM) combined with lenalidomide and dexamethasone (KRd). No prospective studies are yet available that analyzed the efficacy of the KRd combination.MethodsHerein, we report a multicenter prospective observational study on 85 patients who were treated with KRd combination as the second or third line of treatment, according to standard practice.ResultsThe median age was 61 years; high-risk cytogenetic was found in 26% and renal impairment (estimated glomerular filtration rate (eGFR) &lt;60 ml/min) in 17%. After a median follow-up of 40 months, patients received a median number of 16 cycles of KRd, with a median duration of treatment (DoT) of 18 months (range, 16.1–19.2 months). The overall response rate was 95%, with a high-quality response (≥very good partial remission [VGPR]) in 57% of the patients. The median progression-free survival (PFS) was 36 months (range, 29.1–43.2 months). Achievement of at least VGPR and a previous autologous stem cell transplantation (ASCT) were associated with longer PFS. The median overall survival (OS) was not reached (NR); the 5-year OS rate was 73%. Nineteen patients underwent KRd treatment as a bridge to autologous transplantation, obtaining a post-transplant minimal residual disease (MRD) negativity in 65% of cases. The most common adverse events were hematological, followed by infection and cardiovascular events, rarely G3 or higher, with a discontinuation rate for toxicities of 6%. Our data confirmed the feasibility and safety of the KRd regimen in real life

Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma

This multicentre, open-label phase 1/2 trial determined safety and efficacy of weekly carfilzomib plus cyclophosphamide-dexamethasone (wKCyd) in newly diagnosed multiple myeloma (NDMM) patients aged ≥65 years or transplant ineligible. Patients received wKCyd for up to nine 28-day cycles, followed by maintenance with carfilzomib until progression/intolerance. The phase 1 portion used a 3+3 dose-escalation scheme to determine the maximum tolerated dose of weekly carfilzomib: 12 patients received wKCyd with carfilzomib doses of 45, 56 and 70 mg/m 2. The recommended phase 2 dose was established at 70 mg/m 2 and 54 patients (phase 1 and 2) received weekly carfilzomib 70 mg/m 2: 85% of them achieved ≥partial response (PR), 66% ≥very good PR, 30%≥near-complete response (CR) and 15% CR. Responses improved in 40 patients who started maintenance: 98% achieved ≥PR, including 29% CR and 10% stringent CR. After a median follow-up of 18 months, the 2-year progression-free survival and overall survival rates were 53.2% and 81%, respectively. The most frequent grade 3-5 toxicities were neutropenia (22%) and cardiopulmonary adverse events (9%). This is the first study of weekly carfilzomib plus an alkylating agent in elderly patients with NDMM. wKCyd was effective, with an acceptable risk/benefit ratio, and thus can be a valid option in this setting

Human RSPO1/R-spondin1 Is Expressed during Early Ovary Development and Augments β-Catenin Signaling

Human testis development starts from around 42 days post conception with a transient wave of SRY expression followed by up-regulation of testis specific genes and a distinct set of morphological, paracrine and endocrine events. Although anatomical changes in the ovary are less marked, a distinct sub-set of ovary specific genes are also expressed during this time. The furin-domain containing peptide R-spondin1 (RSPO1) has recently emerged as an important regulator of ovary development through up-regulation of the WNT/β-catenin pathway to oppose testis formation. Here, we show that RSPO1 is upregulated in the ovary but not in the testis during critical early stages of gonad development in humans (between 6–9 weeks post conception), whereas the expression of the related genes WNT4 and CTNNB1 (encoding β catenin) is not significantly different between these tissues. Furthermore, reduced R-spondin1 function in the ovotestis of an individual (46,XX) with a RSPO1 mutation leads to reduced β-catenin protein and WNT4 mRNA levels, consistent with down regulation of ovarian pathways. Transfection of wild-type RSPO1 cDNA resulted in weak dose-dependent activation of a β-catenin responsive TOPFLASH reporter (1.8 fold maximum), whereas co-transfection of CTNNB1 (encoding β-catenin) with RSPO1 resulted in dose-dependent synergistic augmentation of this reporter (approximately 10 fold). Furthermore, R-spondin1 showed strong nuclear localization in several different cell lines. Taken together, these data show that R-spondin1 is upregulated during critical stages of early human ovary development and may function as a tissue-specific amplifier of β-catenin signaling to oppose testis determination

Multidifferential study of identified charged hadron distributions in ZZ-tagged jets in proton-proton collisions at s=\sqrt{s}=13 TeV

Jet fragmentation functions are measured for the first time in proton-proton collisions for charged pions, kaons, and protons within jets recoiling against a $Z$ boson. The charged-hadron distributions are studied longitudinally and transversely to the jet direction for jets with transverse momentum 20 $< p_{\textrm{T}} < 100$ GeV and in the pseudorapidity range $2.5 < \eta < 4$. The data sample was collected with the LHCb experiment at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 1.64 fb$^{-1}$. Triple differential distributions as a function of the hadron longitudinal momentum fraction, hadron transverse momentum, and jet transverse momentum are also measured for the first time. This helps constrain transverse-momentum-dependent fragmentation functions. Differences in the shapes and magnitudes of the measured distributions for the different hadron species provide insights into the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb public pages

Study of the B−→Λc+Λˉc−K−B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-} decay

The decay $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ is studied in proton-proton collisions at a center-of-mass energy of $\sqrt{s}=13$ TeV using data corresponding to an integrated luminosity of 5 $\mathrm{fb}^{-1}$ collected by the LHCb experiment. In the $\Lambda_{c}^+ K^{-}$ system, the $\Xi_{c}(2930)^{0}$ state observed at the BaBar and Belle experiments is resolved into two narrower states, $\Xi_{c}(2923)^{0}$ and $\Xi_{c}(2939)^{0}$, whose masses and widths are measured to be $$m(\Xi_{c}(2923)^{0}) = 2924.5 \pm 0.4 \pm 1.1 \,\mathrm{MeV}, \\ m(\Xi_{c}(2939)^{0}) = 2938.5 \pm 0.9 \pm 2.3 \,\mathrm{MeV}, \\ \Gamma(\Xi_{c}(2923)^{0}) = \phantom{000}4.8 \pm 0.9 \pm 1.5 \,\mathrm{MeV},\\ \Gamma(\Xi_{c}(2939)^{0}) = \phantom{00}11.0 \pm 1.9 \pm 7.5 \,\mathrm{MeV},$$ where the first uncertainties are statistical and the second systematic. The results are consistent with a previous LHCb measurement using a prompt $\Lambda_{c}^{+} K^{-}$ sample. Evidence of a new $\Xi_{c}(2880)^{0}$ state is found with a local significance of $3.8\,\sigma$, whose mass and width are measured to be $2881.8 \pm 3.1 \pm 8.5\,\mathrm{MeV}$ and $12.4 \pm 5.3 \pm 5.8 \,\mathrm{MeV}$, respectively. In addition, evidence of a new decay mode $\Xi_{c}(2790)^{0} \to \Lambda_{c}^{+} K^{-}$ is found with a significance of $3.7\,\sigma$. The relative branching fraction of $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ with respect to the $B^{-} \to D^{+} D^{-} K^{-}$ decay is measured to be $2.36 \pm 0.11 \pm 0.22 \pm 0.25$, where the first uncertainty is statistical, the second systematic and the third originates from the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb public pages

Measurement of the ratios of branching fractions R(D∗)\mathcal{R}(D^{*}) and R(D0)\mathcal{R}(D^{0})

The ratios of branching fractions $\mathcal{R}(D^{*})\equiv\mathcal{B}(\bar{B}\to D^{*}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(\bar{B}\to D^{*}\mu^{-}\bar{\nu}_{\mu})$ and $\mathcal{R}(D^{0})\equiv\mathcal{B}(B^{-}\to D^{0}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(B^{-}\to D^{0}\mu^{-}\bar{\nu}_{\mu})$ are measured, assuming isospin symmetry, using a sample of proton-proton collision data corresponding to 3.0 fb${ }^{-1}$ of integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The tau lepton is identified in the decay mode $\tau^{-}\to\mu^{-}\nu_{\tau}\bar{\nu}_{\mu}$. The measured values are $\mathcal{R}(D^{*})=0.281\pm0.018\pm0.024$ and $\mathcal{R}(D^{0})=0.441\pm0.060\pm0.066$, where the first uncertainty is statistical and the second is systematic. The correlation between these measurements is $\rho=-0.43$. Results are consistent with the current average of these quantities and are at a combined 1.9 standard deviations from the predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb public pages