CARFILZOMIB, LENALIDOMIDE AND DEXAMETHASONE IN RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS: THE REAL LIFE EXPERIENCE OF RETE EMATOLOGICA PUGLIESE (REP)

Background: Carfilzomib, lenalidomide and dexamethasone (KRd) has been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) based on ASPIRE clinical trial. However, its effectiveness and safety profile in real clinical practice should be further assessed. Aims: We retrospectively evaluated 120 consecutive RRMM patients treated with KRd, in 9 hematology departments of Rete Ematologica Pugliese (REP), with the aim to evaluate the efficacy and safety with KRd treatment in a real world setting. Methods: Between December of 2015 and August 2018,120 RRMM patients were analyzed.The patients’ baseline characteristics are presented in Table 1. Median patient’s age was 66 years and 41 patients(34%) were older than 70 years. The median number of previous treatment lines was 1 (range 1–11). The 94% of the patients had been already treated with bortezomib-based regimens and 33% with both lenalidomide- and bortezomib-based regimens. Moreover, half of the patients (52%) had a previous autologous stem cell transplant. The median time from the diagnosis to start of treatment with KRd was 40 months (range 5–295) and 30 patients were treated with KRd early (≤18 months from diagnosis).Disease status at the start of treatment with KRd was refractory in 33 patients(29%) and 13 patients(12%) were refractory to lenalidomide. Twenty-four patients(21%) were refractory at last therapy before KRd enrollment. Results: The overall response rate (ORR) was 84%(n = 93),with 23%(25) complete response (CR) and 50%(55) very good partial response(VGPR).The median duration of response was 12,9 months (range, 3,33– 27,7). ORR was higher in patients relapsed after a previous autologous transplant (ASCT;56% vs 37% in those relapsed without prior ASCT;p 0,05).Patients treated in late relapse had a better ORR (44%) vs those in early relapse (19%; p 0,02). After a median follow-up of 13,4 months, median PFS was not reached (NR) and 2y-PFS was 61%, Figure 1. PFS was longer in responding patients (achieving at least PR) to those with less than PR (median PFS NR vs 4,9 months;p 0,0001).Median PFS in patients relapsed after a prior ASCT was NR vs 20 months in those without prior ASCT, (p 0,002).Patients achieving ASCT after KRD had a better PFS in confront to those without ASCT (median NR vs 9 months, p 0,001).Several baseline patient characteristics, such as the III ISS scoring, older age, prior exposure to lenalidomide and early relapse were found to negatively impact PFS.Twenty-eight patients(24%) performed 4 KRd cycles as bridge treatment to ASCT. The 64% of patients reached a VGPR and 67% received ASCT, with 9 upgraded from VGPR to complete response (CR) after ASCT.The treatment discontinuation rate due to adverse events (AEs) was 13%, most commonly related to lenalidomide(8%). KRd dose reduction was necessary in 11% of patients (2,5% for carfilzomib and 8% for lenalidomide).The most frequent AE was neutropenia(43%) and anemia (41%). Infections occurred in 10% of patients.Adverse Cardiovascular toxicity (Atrial fibrillation and pulmonary hypertension)occurred in 8% of patients. Summary/Conclusion: Our analysis confirmed that KRd is effective in RRMM patients. It is well tolerated and applicable to the majority of patients outside clinical trials. A longer PFS was shown in patients 24th Congress of the European Hematology Association 276 | 2019;3:S1 achieving at least a partial response (PR), relapsing after previous ASCT and in those with the possibility to perform ASCT after KRd treatment. Accordingly,KRd should be used as an optimal bridge regimen to ASCT. Previous ASCT should not hamper the option for KRd therap

Renormalization and redundancy in 2d quantum field theories

We analyze renormalization group (RG) flows in two-dimensional quantum field theories in the presence of redundant directions. We use the operator picture in which redundant operators are total derivatives. Our analysis has three levels of generality. We introduce a redundancy anomaly equation which is analyzed together with the RG anomaly equation previously considered by H.Osborn [8] and D.Friedan and A.Konechny [7]. The Wess-Zumino consistency conditions between these anomalies yield a number of general relations which should hold to all orders in perturbation theory. We further use conformal perturbation theory to study field theories in the vicinity of a fixed point when some of the symmetries of the fixed point are broken by the perturbation. We relate various anomaly coefficients to OPE coefficients at the fixed point and analyze which operators become redundant and how they participate in the RG flow. Finally, we illustrate our findings by three explicit models constructed as current-current perturbations of SU(2)_k WZW model. At each generality level we discuss the geometric picture behind redundancy and how one can reduce the number of couplings by taking a quotient with respect to the redundant directions. We point to the special role of polar representations for the redundancy groups.Comment: 59 pages, 5 pdf figures; V3: version equivalent to the version published in JHEP (up to an additional footnote

Human and mouse SYBL1 gene structure and expression

SYBL1 is a gene in the 320 kb human pseudo-autosomal region at the terminus of Xq and Yq. In contrast to other pseudoautosomal genes, SYBL1 is inactivated on one X in every female cell, and is also inactive on the Y of male cells. Hypermethylation of the CpG island associated with the human gene is involved in this phenomenon. In an attempt to further examine its regulation, the genomic organization of the X-linked mouse Sybl1 homolog was analyzed and compared with the human gene. Human and mouse show the same exon number, exon-intron junctions and a highly conserved basal promoter. The structural and functional conservation of basal regulatory regions suggests that inactivation is imposed by similar auxiliary epistatic regulatory mechanism. (C) 1999 Elsevier Science B.V. All rights reserved

Microsatellite instability and mutation analysis among southern Italian patients with colorectal carcinoma: detection of different alterations accounting of MLH1 and MSH2 inactivation in familial cases

Background: Microsatellite instability (MSI) is due to defective DNA mismatch repair (MMR) and has been detected at various rates in colorectal carcinoma (CRC). The role of MSI in colorectal tumorigenesis was assessed further in this study by both microsatellite analysis of two CRC subsets [unselected patients (n = 2 15) and patients <50 years of age (n = 95)], and mutation screening of the two major MMR genes MLH1 and MSH2 among familial CRC cases. Patients and methods: PCR-based microsatellite analysis was performed on paraffin-embedded tissues. In CRC families, MLH1/MSH2 mutation analysis and MLH1/MSH2 immunostaining were performed on germline DNA and MS1+ tumour tissues, respectively. Results: The MSI+ phenotype was detected in 75 (24%) patients. with higher incidence in early-onset or proximally located tumours. Among 220 patients investigated for family cancer history, MSI frequency was markedly higher in familial 118/27 (67%)] than in sporadic [32/193 (17%)] cases. Three MLH1 and six MSH2 germline mutations were identified in 14 out of 36 (39%) CRC families. Prevalence of MLH1/MSH2 mutations in CRC families was significantly increased by the presence of: (i) fulfilled Amsterdam criteria: (ii) four or more CRCs; or (iii) one or more endometrial cancer. While MSH2 was found mostly mutated, almost all [8/9 (89%)] familial MSI+ cases with loss of the MLH1 protein were negative for MLH1 germline mutations. Conclusions: Both genetic (for MSH2) and gene-silencing (for MLH1) alterations seem to be involved in CRC pathogenesis