MPR Group Research Articles

Mycophenolate Mofetil with Steroid, a Reasonable Alternative to Current First-line Therapy, for Idiopathic Membranous Nephropathy in Resource-constrained Settings: A Randomized, Open-label Study.

The modified Ponticelli regimen (mPR) is a first-line therapy in patients with idiopathic membranous nephropathy (IMN); however, it has a less favorable safety profile. Though mycophenolate mofetil (MMF) + steroid (S) is not recommended by Kidney Disease Improving Global Outcomes guidelines, it can be used as an alternative to mPR due to higher tolerability and steroid-sparing effect. Thus, we compared the safety and effectiveness of MMF + S and mPR regimens in patients with IMN. This randomized, open-label study enrolled patients with adult-onset nephrotic syndrome (NS) and biopsy-proven IMN. Forty-two patients were allocated to MMF + S group (MMF 1 gm twice daily + oral prednisolone 0.5 mg/kg/day; n = 21) and mPR group [methylprednisolone (1 gm intravenous) for 3 days followed by alternating monthly cycles of oral prednisolone (0.5 mg/kg/day) for the next 27 days and cyclophosphamide (2 mg/kg/day) for 6 months; n = 21]. The primary outcome measure was change in urinary protein creatinine ratio (UPCR). At 6 months, both groups demonstrated a significant increase in serum albumin levels and estimated glomerular filtration rate (eGFR) (both p-values <0.0001) as well as a decrease in 24-hour proteinuria (MMF + S group: p-value = 0.003, and mPR group: p-value <0.0001) and UPCR (both p-values <0.0001). However, the groups did not differ in any of these parameters at any of the monthly follow-up visits. Moreover, the groups did not differ significantly in terms of the composite remission rates (61.91% for MMF + S group and 71.43% for mPR group). MMF + S and mPR had comparable tolerability and effectiveness, with MMF-associated advantage of reduced steroid exposure.

Clinical Outcomes in Patients With DLBCL Treated With R-CHOP According to Radiotherapy and Interim PET Response.

Interim positron emission tomography/computed tomography (PET/CT) scan is a valuable tool for assessing the early metabolic response to chemotherapy in diffuse large B-cell lymphoma (DLBCL). Although radiotherapy is an effective treatment for lymphoma, especially for local tumor control, the role of consolidative radiotherapy in diffuse large B-cell lymphoma (DLBCL) remains controversial. This study analyzed the clinical outcomes of patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), stratified by interim PET response and the administration of radiotherapy. We conducted a retrospective review of 107 patients with DLBCL treated with R-CHOP chemotherapy between January 2012 and December 2016. Overall survival (OS), recurrence-free survival (RFS), and freedom from disease progression (FFDP) were calculated using the Kaplan-Meier method and compared using the log-rank test. Forty-six patients were included in this analysis, with a median follow-up time of 65.9 months (range=4.7-125.3 months). The metabolic CR (mCR) group exhibited superior OS, RFS, and FFDP compared with the metabolic PR (mPR) group (p=0.003, p=0.001, and p=0.008, respectively). The 1-, 2-, and 5-year FFDP were 92.97%, 89.3%, and 85.6%, respectively, in the mCR group and 78.6%, 61.9%, and 44.2%, respectively, in the mPR group. In subgroup analysis, the FFDP of the mPR group without radiotherapy was significantly lower than that of the other groups (mCR with/without radiotherapy and mPR with radiotherapy, p=0.001). Consolidative radiation therapy using interim PET can benefit patients who do not achieve mCR. Further well-controlled prospective randomized trials are required.

Bone indices and body weight changes of ovariectomized rats treated with&lt;i&gt; Marantodes pumilum&lt;/i&gt; var. &lt;i&gt;Alata&lt;/i&gt;

Marantodes pumilim var. alata (MPva) is a popular female aphrodisiac and known source of phytoestrogens. It is traditionally used to manage postmenopausal crisis and preserve bone health in women. The study aims to investigate the effects of MPva on bone indices and bodyweight of post-menopausal rats. Thirty female Sprague-Dawley rats were divided into groups (n=6): Healthy control (Sham); ovariectomized control (OVXC); Estrogen treatment (ERT); plant leaf extract treatment (MPr) and plant root extract treatment (MPv) groups. All rats (except the Sham-operated group) were ovariectomized. After 2-weeks healing period, the ERT group was treated with 64.5 μg/kg estrogen while MPv and MPr groups received pre-determined optimal daily dose of MPva leaf and root extracts, respectively. Changes in bodyweight of rats were monitored through an eight-weeks treatment period after which rats were euthanized for testing of bone parameters. Both leaves and roots of MPva (20 mg/kg) were found to show optimal preservation of bone mineral density and mechanical strength. Untreated estrogen-deficient rats (OVXC) showed significant weight-gain when compared with the healthy control (Sham) (p&lt;0.05). Treatment with MPva leaf and root extracts, similar to treatment with estrogen, significantly suppressed weight-gain observed in the estrogen-deficient (OVXC) group (p&lt;0.05). In conclusion, treatment with MPva leaf and root extracts preserved bone strength. In addition, it suppressed weight gain in postmenopausal rats, an outcome that makes MPva more beneficial to postmenopausal women that may experience weight gain.

Exploration of biomarkers in potentially resectable stage IIIB NSCLC patients receiving neoadjuvant chemoimmunotherapy.

e20591 Background: Non–small cell lung cancer (NSCLC) is one of the main leading causes of cancer mortality in the world. NSCLC is incurable in most patients with potentially resectable locally advanced stage IIIB disease. Numerous studies suggest that advantageous chemoimmunotherapy is a promising treatment for resectable NSCLC. The determination of PD-L1, T-cell receptor (TCR) repertoire and tumor mutational burden (TMB) have been reported to predict the response to immunotherapy. However, the value of pathologic response determination in the context of neoadjuvant chemoimmunotherapy in resectable stage IIIB NSCLC is limited. Therefore, it is necessary to identify biomarkers for the prediction of the benefit from neoadjuvant chemoimmunotherapy in patients with potentially resectable stage IIIB NSCLC. Methods: A total of 15 patients with potentially resectable clinical stage IIIB NSCLC were enrolled into the study receiving neoadjuvant sintilimab (200mg IV Q3W) plus chemotherapy therapies for 4-6 weeks followed by surgery. All peripheral blood and tissue samples were collected and detected by using TCR repertoire sequencing before and after chemoimmunotherapy. The patients were divided into MPR group (n=5) and non-MPR group (n=10) according to MPR (&lt;10% viable tumour at resection) as an index. Furthermore, TMB spectra of 1021-gene panels and PD-L1 immunohistochemical staining were performed in paraffin-embedded human NSCLC tissue before neoadjuvant chemoimmunotherapy. The Pearson correlation coefficient method was used to analyze correlation. The ROC analysis were performed using “pROC” R package. Results: In baseline tissue samples, the levels of TMB and NAD were higher in MPR compared with non-MPR groups (P=0.0328, P=0.015, respectively). The negative correlation was existed between pretreatment tissue TCR richness and TMB in non-MPR group (P=0.028, R=-0.66). In MPR group, TCR clones and evenness showed significant difference (P=0.00237, P=0.04658, respectively). In non-MPR group, the TCR repertoire of tissue in posttreatment showed significant difference compared with those of pretreatment, including clones (P=1.04x10-6), shannon’s diversity (P=0.00142), evenness (P=0.00433), richness (P=0.00591). The clinical data showed that MPR patients with DDR mutation had longer DFS after sintilimab plus chemotherapy therapies (18.4±5.41 months, X-squared=9.8, P=0.02034). DDR mutation, TMB and TCR richness revealed better sensitivity and specificity to classify patients achieving MPR after neoadjuvant chemoimmunotherapy (AUC=1.000, AUC=0.796, AUC=0.773, respectively). Conclusions: This study confirmed the superiority of neoadjuvant chemoimmunotherapy in patients with potentially resectable stage IIIB NSCLC in terms of MPR. TCR repertoire, TMB and DDR mutation were associated with pathologic response to neoadjuvant chemoimmunotherapy as biomarkers for effective anti-tumor immunity. Clinical trial information: ChiCTR2000040673 .

Effect of multi-omics analysis on tumor ecosystem during neoadjuvant dose-limiting chemotherapy combination with sequential PD-1 blockade for patients with esophageal cancer.

e16085 Background: Patients with esophageal cancer benefited from neoadjuvant chemotherapy combined with immunotherapy. However, the sequence of administration during neoadjuvant therapy remains under considerable debate. Methods: A study on 23 enrolled patients with esophageal cancer who received 2 cycles of neoadjuvant treatment of dose-limiting chemotherapy combined with sequential pembrolizumab and 2 cycles of adjuvant treatment of dose-limiting chemotherapy combined with sequential pembrolizumab was carried out. Serial plasma samples were collected and subjected to T cell receptor (TCR) sequencing. Tissues with pre- and post-neoadjuvant therapy were obtained and performed with whole-exome sequencing and transcriptome sequencing. Results: After neoadjuvant therapy, the percentage of patients with a pathological major response (MPR) was 39.1% (9/23), consisting of 21.7% (5/23) completed pathological response (cPR). TCR sequencing analysis showed that the peripheral blood-dominated TCR clones significantly augmented during the neoadjuvant treatment. Tumor mutational burden (TMB) was higher in the MPR group than in the non-MPR group at baseline. In addition, infiltrating CD8+ T cells increased and regulatory T (Treg) cells decreased in the MPR group after neoadjuvant therapy. While Treg cells increased in the non-MPR group after neoadjuvant treatment. Conclusions: Dominated TCR clones increased during the neoadjuvant limited-dose chemotherapy stage, which would contribute to sequential PD-1 blockade. Additionally, TMB, CD8+ T cells, and Treg cells are associated with clinical benefits during treatment.

1256P Three courses of neoadjuvant camrelizumab combined with chemotherapy in locally advanced esophageal squamous cell carcinoma (ESCC): A prospective phase II clinical trial

Neoadjuvant chemotherapy with anti-PD-1 antibody has favorable effect for locally advanced ESCC. However, these trials only applied two courses of neoadjuvant protocols. The efficacy and safety of three courses regimen are poorly known. This study explored the three courses of camrelizumab plus chemotherapy for treating locally advanced ESCC in a prospective phase II trial. We planned to recruit locally advanced ESCC patients to received three courses of camrelizumab (200mg every 3 weeks) plus nab-paclitaxel (260 mg/m2 every 3 weeks) and capecitabine (1250 mg/m2 every 3 weeks) before undergoing surgery. The first endpoint was complete pathological response. The second endpoint was safety and feasibility. To further explore the biomarkers for predicting the efficacy, we performed extensive analyses using immunohistochemistry, WES and mutiplex immunofluorescence. From May 2020 to December 2021, a total of 47 patients was enrolled in Sun Yat-sen university cancer center. The ORR was 83%, 42 patients received surgery and R0 resection was achieved in all cases. 33.3% patients had a pCR and 64.3% had an MPR. The median follow-up was 12 months (range, 3-22 months). Only one patient died at 12th month after surgery due to cardiovascular diseases, and one patient had recurrence in the left main bronchus lymph node at 12th month. 1-year OS rate and 1-year DFS rate was 97.3% and 92.1%, respectively. The most common adverse events were grade 1-2, which did not delay the operation. The density of CD56dim NK cells in pretreatment tissues was significant higher in pCR+MPR group than non-responders group(P=0.0085). And after neoadjuvant treatment, the density of CD56dimNK cells significantly decrease in pCR+MPR group (P=0.00019). However, the PD-L1 expression and TMB had no difference between the two groups (P = 0.165, P = 0.627, respectively). Three courses of neoadjuvant camrelizumab combined with chemotherapy in locally advance ESCC had a favorable pathological response, with a manageable safety profile. Three courses regimen may achieve a better survival and patients with a higher density of CD56dim NK cells might benefit greatly from the regimen.

Rapid Automatized Naming as a Universal Marker of Developmental Dyslexia in Italian Monolingual and Minority-Language Children.

Rapid Automatized Naming (RAN) is considered a universal marker of developmental dyslexia (DD) and could also be helpful to identify a reading deficit in minority-language children (MLC), in which it may be hard to disentangle whether the reading difficulties are due to a learning disorder or a lower proficiency in the language of instruction. We tested reading and rapid naming skills in monolingual Good Readers (mGR), monolingual Poor Readers (mPR), and MLC, by using our new version of RAN, the RAN-Shapes, in 127 primary school students (from 3rd to 5th grade). In line with previous research, MLC showed, on average, lower reading performances as compared to mGR. However, the two groups performed similarly to the RAN-Shapes task. On the contrary, the mPR group underperformed both in the reading and the RAN tasks. Our findings suggest that reading difficulties and RAN performance can be dissociated in MLC; consequently, the performance at the RAN-Shapes may contribute to the identification of children at risk of a reading disorder without introducing any linguistic bias, when testing MLC.

Clinical study of circulating tumor cells in monitoring the efficacy of neoadjuvant immunotherapy for non-small cell lung cancer

Objective: To investigate the changes of CTCs and the correlation between the changes of CTCs and the clinical efficacy of neoadjuvant immunotherapy for non-small cell lung cancer (NSCLC). Methods: A retrospective case-control study was conducted to collect the data of 23 patients with NSCLC who received neoadjuvant immunotherapy in the Third Xiangya Hospital from June 2018 to December 2019. They were 35-76 years old with a median age of 52 years old, including 13 male patients and 10 female patients. The CTCs value, evaluation results from response evaluation criteria in solid tumor (RECIST) and major pathological response were evaluated before treatment, after neoadjuvant immunotherapy and after operation. Mann Whitney U test was used for the comparison between the two groups, Wilcoxon test was used for the comparison of association samples, and Kruskal Wallis test was used for the comparison between multiple samples. Results: The CTCs value was positively correlated with tumor progression, that the CTCs value of ⅡB group, ⅢA group and ⅢB group was 10.69 (3.87) FU/3 ml, 12.90 (2.24) FU/3 ml and 16.04 (3.43) FU/3 ml, and the difference was statistically significant (χ2=7.829, P=0.020). Then CTCs decreased to 7.60(4.79) FU/3 ml significantly (Z=4.197,P=0.000), and decreased to 6.22(2.80) FU/3 ml significantly again after surgery(Z=-2.950,P=0.005). In RECIST results, the CTCs value of CR group, PR group and SD group was 12.90(3.79)FU/3 ml, 12.52(3.96) FU/3 ml and 13.58(5.11) FU/3 ml,and no significant difference before treatment (χ²=1.806, P=0.405). After neoadjuvant immunotherapy, the CTCs of CR group decreased to 6.22(3.87) FU/3 ml significantly (Z=-4.950, P= 0.000), and also PR group to7.32(4.31) FU/3 ml (Z=-3.180, P=0.001) or SD group to (Z=-2.023, P=0.043). There was no significant difference between CR group and PR group (Z=-0.838, P=0.402), but significant difference between SD group and CR/PR group (Z=-1.922, P=0.050). After operation, the CTCs of CR, PR and SD group decreased to 6.09(3.43) FU/3 ml, 6.40(1.82) FU/3 ml and 9.20(5.16) FU/3 ml,and there was no significant difference to preparation in CR group and PR group, but significant difference in SD group (Z=-2.023, P=0.043). There was no significant difference between CR group and PR group (Z=-1.134, P=0.257), but significant difference between SD group and CR/PR group (Z=-1.624, P=0.014). Before treatment,CTCs of MPR group and non-MPR group were 11.98(4.14) FU/3 ml and 13.54(4.76) FU/3 ml,and there was no significant difference between them (Z=-1.354, P=0.176). After neoadjuvant immunotherapy, the CTCs of MPR group decreased to 6.36(2.65) FU/3 ml significantly (Z=-2.934, P=0.001) and also in non-MPR group to 10.88(2.80) FU/3 ml (Z=-2.840, P=0.003); but there was significant difference between MPR group and non-MPR group (Z=-3.693, P=0.000), and also the change of CTCs between two groups (Z=-2.770, P=0.006). After operation, the CTCs of MPR group decreased to 5.40(1.33) FU/3 ml insignificantly (Z=-0.533, P=0.594) but significantly to 7.05(3.80) FU/3 ml in non-MPR group (Z=-2.734, P=0.030), and significant difference between them (Z=-1.900, P=0.011). Conclusion: The value of CTCs is negatively correlated with the efficacy (RECIST and MPR) of neoadjuvant immunotherapy for NSCLC, which can be used for clinical efficacy evaluation of neoadjuvant immunotherapy.

Pathological nodal disease defines survival outcomes in patients with lung cancer with tumour major pathological response following neoadjuvant chemotherapy.

Major pathological response (MPR) is prognostic of outcomes for patients with non-small-cell lung cancer following neoadjuvant chemotherapy and is used as the primary end point in neoadjuvant immunotherapy trials. We studied the influence of pathological nodal disease on patterns and timing of recurrence among patients with MPR. Patients treated with neoadjuvant chemotherapy for stages I-III non-small-cell lung cancer were identified. Surgical specimens were histopathologically examined for tumour viability, categorized as ≤10% viability (MPR) or >10% (NoMPR). Overall survival and disease-free survival were evaluated with emphasis upon MPR and pathological nodal disease. Among 307 patients, 58 (19%) had MPR within primary tumour and 42 (14%) had MPRypN0. In the MPR group, the frequency of cN0 and cN+ disease was 18 (31%) and 40 (69%); similarly, the frequency of ypN0, ypN1 and ypN2 was 72% (42/58), 16% (9/58) and 12% (7/58), respectively. When evaluating only those with MPR, recurrence rates among those with MPRypN0, MPRypN1 and MPRypN2 were 33% (14/42), 44% (4/9) and 71% (5/7) (P = 0.16). The median time-to-recurrence in MPRypN0, MPRypN1 and MPRypN2 was 40, 10 and 14 months (P = 0.006). Distant recurrences were less common among those with MPRypN0 [MPRypN0, 26% (11/42); MPRypN1, 44% (4/9); MPRypN2, 71% (5/7); P = 0.047]. Though the median disease-free survival was prolonged among those with MPR vs NoMPR (120 vs 25 months, P < 0.0001), only those with MPRypN0 had prolonged disease-free survival in comparison to other groups upon pairwise comparisons, while MPRypN+ experienced no benefit. MPRypN0 represents the most favourable surrogate end point following neoadjuvant chemotherapy. Patients with ypN1-2 are at the risk of early recurrence regardless of primary tumour MPR, warranting intensive surveillance and consideration for additional adjuvant therapy. We highlight that MPRypN0 is the most rigorous end point and should be considered as a surrogate end point in future neoadjuvant trials.

Comparative anti-osteoporotic properties of the leaves and roots of Marantodes pumilum var. alata in postmenopausal rat model

BackgroundMarantodes pumilum var. alata (MPva), popularly known as Kacip Fatimah, is widely used to maintain female reproductive health, facilitate post-partum recovery and manage symptoms of menopause and osteoporosis in South-East Asia. This study aims to further evaluate the osteoprotective potential of MPva in view of reports of its bone-protective properties in postmenopausal condition. MethodsThirty female Sprague-Dawley rats were sorted into 5 groups (n = 6) namely: MPv (leaf treatment); MPr (root treatment); ERT (estrogen treatment); OVXC (untreated ovariectomized control) and Sham (untreated sham-operated control). All rats (except the Sham) were ovariectomized to induce a state of estrogen deficiency that simulates menopause. Two weeks after ovariectomy, the rats were treated for 8 weeks with oral gavages of estrogen and plant extracts. The ERT group received 64.5 μg/kg/day dose of estrogen while MPv and MPr groups received 20 mg/kg/day dose of leaf and root extracts, respectively. At the end of treatment, left femora were excised from euthanized rats and investigated for changes in bone micro-architecture, mineral density, and biomechanical properties. ResultsBone volume fraction, degree of anisotropy and structure-model-index of bone were significantly improved (p < 0.05) in the MPv group compared to OVXC. Breaking force and maximum stress of bone were also significantly higher (p < 0.05) in the MPv group compared to the OVXC. ConclusionTreatment with MPva leaf protected bone microarchitecture and density against osteoporosis-related changes in postmenopausal rats. Similar to estrogen, the protective effects of MPva leaf translated into better-enhanced bone mechanical properties compared to the root treatment.

Bone turnover and oxidative stress markers in estrogendeficient rats treated with &lt;i&gt;Marantodes pumilum&lt;/i&gt; leaves and roots: A comparative study

Purpose : To investigate the relative changes in bone turnover and oxidative status markers of estrogen-deficient rats treated with Marantodes pumilum var. alata (MPva) leaf and root extracts. Methods : Thirty-six female Sprague-Dawley rats were divided into 6 groups (n = 6), namely: baseline (BL); placebo surgery (PS); ovariectomized control (OVXC); estrogen treatment (ERT); leaf extract treatment (MPv); and root extract treatment (MPr). Rats in all groups, except BL and PS, were ovariectomized to induce menopause. Through the oral route, ERT received 64.5 μg/kg/day estrogen (Premarin®); MPv received 20 mg/kg/day leaf extracts of MPva; MPr received 20 mg/kg/day root extract of MPva; while BL, OVXC, and PS served as untreated controls. At the end of 8 weeks treatment, blood and bone samples were collected for assay of bone turnover markers (osteocalcin and pyridinoline) and oxidative status markers (4-hydroxynonenal, superoxide dismutase, and glutathione peroxidase) using enzyme-linked immunosorbent assay (ELISA). Results : Significantly higher (p < 0.05) bone level of glutathione peroxidase was seen in MPv when compared with BL and OVXC. MPv also showed lower bone level of pyridinoline (p<0.05) compared to OVXC. Bone level of 4-hydroxynonenal in both MPv and MPr groups was significantly reduced (p < 0.05) when compared with OVXC. Conclusion : MPva leaf showed more remarkable effects on bone turnover and oxidative stress markers of ovariectomized rats than its roots and estrogen treatment. Thus, the use of MPva leaf, as an alternative to estrogen for treating postmenopausal osteoporosis, would be preferred to its roots. Keywords : Phytoestrogens, Osteoporosis, Marantodes pumilum

Hip and other fragility fracture incidence in real-world teriparatide-treated patients in the United States

SummaryThis study demonstrates real-world effectiveness of teriparatide in reducing the risk of hip and other fragility fractures. Fracture incidence significantly decreased as adherence and persistence increased for any clinical, vertebral, nonvertebral, and hip fractures among patients who were observed for 2 years after teriparatide initiation.IntroductionExamine the relationship of treatment adherence and persistence to teriparatide with hip and other fractures.MethodsTruven MarketScan Research Databases, 2004 through 2014, provided teriparatide users ≥18 years old with continuous coverage 12 months pre- and 24 months post-teriparatide prescription. Adherence (medication possession ratio, MPR) groups were defined as high (≥0.80), medium (0.50 ≤ MPR < 0.80), and low (<0.50). Persistence, allowing for ≤90-day gaps between prescriptions, was defined as 1–6, 7–12, 13–18, and 19–24 months. Fracture incidence was summarized and compared by using ANOVA and logistic regression models; the effects of adherence were examined with Cox proportional hazard models with time-dependent covariates for teriparatide exposure.ResultsAmong 14,284 teriparatide subjects, mean age was 68.4 years, 89.8% were female, and 29.6% had a fracture in the previous year; these characteristics were similar across MPR and persistence groups. The effects of adherence and persistence to teriparatide were statistically significant (P < .001) for all fracture types except wrist (P ≥ .125). By logistic regression, high vs low adherence was associated with reduced risk for any (OR = 0.67; P < .001); vertebral (OR = 0.64; P < .001); nonvertebral (OR = 0.71; P < .001); and hip fractures (OR = 0.52; P < .001) and longer (19–24 months) vs shorter persistence (1–6 months) was associated with reduced risk for any (OR = 0.63, P < .001); vertebral (OR = 0.56, P < .001); nonvertebral (OR = 0.69, P < .001); and hip fractures (OR = 0.48, P < .001). Cox models revealed a significantly reduced risk between high and low adherence for any (OR = 0.69, P < .001); vertebral (OR = 0.60, P < .001); nonvertebral (OR = 0.77, P < .001); and hip fractures (OR = 0.55, P < .001).ConclusionFracture incidence significantly decreased as persistence and adherence to teriparatide increased.

Doublet Vs Triplet Lenalidomide-Containing Regimens in Newly Diagnosed Myeloma Patients, Younger or Older Than 75 Years: Subgroup Analysis of a Phase III Study

Introduction : a formal comparison between Lenalidomide-Dexamethasone (Rd) and Lenalidomide-Prednisone plus Melphalan (MPR) or Cyclophosphamide (CPR) has not been performed yet. We compared Rd vs. MPR vs. CPR in newly diagnosed multiple myeloma (NDMM) patients ≥65 years old in a multicenter phase III trial. Per protocol, upfront dose reductions of Dexamethasone, Melphalan and Cyclophosphamide were performed, according to patients age ( ≤75 years vs. >75 years). The primary endpoint was progression-free survival (PFS).Methods : 662 patients with NDMM were randomized to receive nine 28-day cycles of Rd (n=222), MPR (n=218) or CPR (n=222). Rd: lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15,22 in patients 65-75 years old and 20 mg in those >75 years; MPR: lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in patients 65-75 years old and 0.13 mg/Kg in patients >75 years; prednisone 1.5 mg/Kg for 4 days; CPR: lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in patients 65-75 years old and 50 mg every other day in patients >75 years; prednisone 25 mg every other day. After induction, patients were randomized to receive maintenance with lenalidomide alone (R) or with prednisone (RP).Results : Patients characteristics were well balanced. Eighty-three (37%) patients in the Rd, 86 (39%) in the MPR and 80 (36%) in the CPR groups were older than 75 years. In intention to treat analysis, after a median follow-up of 31 months, no difference in PFS and overall survival (OS) was observed. Median PFS was 23 months in Rd, 27 months in MPR and 23 months in CPR (Rd vs MPR p=0.216; Rd vs CPR p=0.872; MPR vs CPR p=0.148). Median OS was not reached and was 73% in Rd, 67% in MPR and 72% in CPR at 3 years (Rd vs MPR p=0.663; Rd vs CPR p=0.754; MPR vs CPR p=0.448). A subgroup analysis, according to age was performed. No difference in response rate was observed. In patients ≤75 years, median PFS was 23 in Rd, 30 in MPR and 23 months in CPR (Rd vs MPR, p<0.04; Rd vs CPR p=0.897; MPR vs CPR, p<0.05).Median OS was not reached and was 75% in Rd, 76% in MPR, 77% in CPR at 3 years (Rd vs MPR p=0.251; Rd vs CPR p=0.280; MPR vs CPR p=0.975). In patients >75 years, no PFS difference was noticed: median PFS was 22 in Rd, 18 in MPR, 21 months in CPR (Rd vs MPR p=0.572; Rd vs CPR p=0.699; MPR vs CPR p=0.914). An OS advantage was reported with Rd: median OS was not reached in Rd patients, and was 37 and 43 months in the MPR and CPR groups, respectively (Rd vs MPR p=0.04; Rd vs CPR p=0.430; MPR vs CPR p=0.323). The rate of at least one hematologic grade 3-4 adverse event was 29% in Rd, 66% in MPR, 33% in CPR patients ≤ 75 years and 29% in Rd, 70% in MPR, 33% in CPR patients > 75 years (MPR vs Rd/CPR p< 0.0001). No difference was observed in extra-hematologic adverse events: 25% in Rd, 24% in MPR and 25% in CPR patients ≤75 years; 29% in Rd, 35% in MPR, 34% in CPR patients >75 years.Conclusion : this trial compared for the first time Rd, MPR and CPR in elderly NDMM. In all patients, the addition of alkylating agent to Lenalidomide-steroid combination did not show any advantage on PFS and OS. In a subgroup analysis, safety and efficacy data suggest that triplet regimens may be indicated in patients ≤75 years, while a doublet regimens for those >75 years. The MPR combination showed a PFS advantage in patients ≤75 years, with a higher incidence of hematologic toxicity and SPM. In patients >75 years an OS advantage was reported with Rd, mainly due to a higher efficacy of salvage treatments. Updated results will be presented at the meeting. DisclosuresOff Label Use: Use of Lenalidomide as off label. Bringhen:Onyx: Consultancy; Merck Sharp & Dohme: Membership on an entity’s Board of Directors or advisory committees; Novartis: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria. Offidani:Mundipharma: Honoraria; Sanofi: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Patriarca:Merck Sharp & Dohme: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Boccadoro:Onyx: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Janssen and Cilag: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Palumbo:Onyx Pharmaceuticals: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Honoraria; Amgen: Consultancy, Honoraria; Array BioPharma: Honoraria.

The frozen–thawed embryo transfer timing determined by serum progesterone level: a retrospective follow-up study

ObjectiveTo compare the reproductive outcomes of frozen–thawed embryo transfer (FET) in nature cycle utilizing monitoring ovulation regimen (MOR) and monitoring progesterone (P) level regimen (MPR). Study designA retrospective analysis of records of 224 women who received FET procedures. Result(s)MPR was used in 60.3% (135/224) of cycles and MOR in 39.7% (89/224) of cycles. The clinical pregnancy rate per transfer was 63.0% in the MPR group and 48.3% in the MOR group (p=0.030). The implantation rates were 42.6% and 35.1%, respectively (p=0.001). The ongoing pregnancy rates per transfer (at 12 weeks’ gestation) were 54.1% and 41.6%, respectively (p>0.05). A logistic regression analysis showed that the type of natural cycle regimen was a predictor of clinical pregnancy rate (odds ratio, 1.996; 95% confidence interval, 1.123-3.549; p=0.019). Other significant variables affecting clinical pregnancy rate was number of top-quality embryos transferred. Conclusion(s)Performing FET using MPR could achieve higher clinical pregnancy rate compared with MOR in a group of patients with the comparable demographic and cycle characteristics profile.

PFS2 In Elderly Patients With Newly Diagnosed Multiple Myeloma (NDMM): Results From The MM-015 Study

IntroductionIn a phase 3 trial of transplant non-eligible elderly (≥ 65 yrs) patients (pts) with NDMM, the combination of melphalan-prednisone-lenalidomide (LEN) followed by LEN maintenance (MPR-R) reduced the risk of progression by 60% compared with 9 cycles of MP (HR=0.40; P < 0.001) and by 51% compared with 9 cycles of MPR (HR=0.49; P < 0.001) (Palumbo, NEJM. 2012). The progression-free survival (PFS) benefit was seen in all patient types. With a median follow-up of 53 mos, the median overall survival (OS) was similar across the 3 treatment (Tx) groups (54 mos for MPR-R vs. 52 mos for MPR vs. 55 mos for MP) (Dimopoulos, ASH 2012; abstract 944). The similar OS benefit seen across the 3 arms could be due in part to the availability of more effective Tx options in subsequent lines of therapy. Assessment of PFS2, defined as the time from initial randomization to time of objective disease progression (PD) after next-line of therapy or death from any cause, has recently been proposed as a surrogate for OS, particularly for trials evaluating maintenance Tx (EMA guideline, www.ema.europa.eu). Therefore, data from MM-015 were analyzed to estimate PFS2 in pts treated with MPR-R, MPR, or MP. MethodsThe MM-015 study design has been previously described (Palumbo, NEJM. 2012). Refractory multiple myeloma pts who progressed during MM-015 study could receive LEN 25 mg (D1–21/28-day cycle) ± dexamethasone 40 mg (on days 1–4, 9–12, and 17–20) as part of an open-label extension phase, or any other anti-myeloma Tx outside of the protocol as part of the follow-up phase. The data of PD following 2nd-line Tx was not collected prospectively; therefore, the start of 3rd-line Tx was used as a surrogate for analyzing the PFS2 endpoint. The assessment included data up to July 31, 2012 (median follow-up: 53 mos after initial randomization). ResultsA total of 459 pts were randomized to MPR-R (n= 152), MPR (n= 153), or MP (n= 154). At the time of the data cut-off, fewer pts in the MPR-R group had started 2nd-line Tx (53%) compared with the MPR and MP groups (77% and 82%, respectively) due to the improved PFS seen with MPR-R in the 1st-line setting. Most pts in the MP group “crossed over” to receive LEN as 2nd-line Tx (72%); choice of 2nd-line Tx in the MPR-R group was heterogeneous (Table). Median PFS2 was significantly higher with MPR-R (39.7 mos) vs. MP (28.5 mos; HR=0.71; log-rank P = 0.013) (Figure). The safety profile of continuous therapy with LEN was predictable and manageable with little evidence of cumulative toxicity and low second primary malignancy risk (Delforge, IMW 2013: abstract O-17). [Display omitted] ConclusionPFS2 was markedly improved in the MPR-R group vs. the MP group. LEN provided a durable progression-free interval also when including the impact of 2nd-line Tx, confirming the clinical benefits of continuous LEN Tx. The benefit of MPR-R was apparent regardless of subsequent Tx; long-term treatment with LEN did not affect the efficacy of subsequent therapy. Use of continuous LEN in the 1st-line setting in combination with MP is more beneficial than sequential use of MP and LEN. PFS and PFS2 were improved with MPR-R; OS was similar among the 3 Tx groups; the reason for this is unclear, but may be related to the impact of subsequent Tx (i.e., 3rd and 4th line), which was more frequently needed in the MPR and MP groups. Disclosures:Dimopoulos:Orthobiotech: Honoraria; Celgene Corporation: Honoraria. Off Label Use: Lenalidomide in the frontline and maintenance treatment of multiple myeloma. Petrucci:Celgene Corporation: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Catalano:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yu:Celgene Corporation: Employment, Equity Ownership. Grote:Celgene Corporation: Employment, Equity Ownership. Jacques:Celgene Corporation: Employment, Equity Ownership. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

Efficacy and Safety Of Melphalan and Prednisone In Combination With Thalidomide, Bortezomib Or Lenalidomide In Newly Diagnosed Transplant-Ineligible Multiple Myeloma Patients: A Single Center Experience

BackgroundThe introduction of new agents has substantially changed the management of patients with multiple myeloma (MM). PATIENTS AND METHODS: We evaluated retrospectively 69 symptomatic newly diagnosed transplant-ineligible MM patients treated at our Institute, between 2004 and 2012, with Melphalan and Prednisone (MP) plus Thalidomide (MPT; 23 patients) or plus Bortezomib (MPV; 30 patients) or plus Lenalidomide (MPR; 16 patients). There were 37 men and 32 woman, median age was 73 years (range 65-84) with 20 patients >75 years, 19 (27.5%) were in stage III according to ISS, 12 (17%) had renal failure (creatinine >1.5 mg/dl at baseline), 7 (10%) an underlying diabetes mellitus and 36 (52%) a cardiovascular disease. Melphalan was given at 9 mg/m2 and Prednisone at 60 mg/m2 orally on days 1-4; Bortezomib at 1.3 mg/m2 intravenously on days 1, 4, 8, 11, 22, 25, 29, 32 for the first 4 cycles and thereafter on days 1, 8, 15, 22; Lenalidomide at 10 mg on days 1-21 and Thalidomide 100 mg/daily were administered orally. All patients received antibacterial prophylaxis; thromboprophylaxis and antiviral prophylaxis were administered to patients treated with IMIDs and Bortezomib, respectively. AimsTo evaluate the safety and efficacy within the MPT-, MPV- and MPR-treated groups. ResultsThe overall response rates ( ≥ partial response), according to the IMWG criteria, were 20/23 (87%) in the MPT group, 26/30 (87%) in the MPV group, 11/16 (68%) in the MPR group (including 3, 9, 2 very good partial response and 2, 3, 2 complete response/near complete response, respectively). The median PFS was 29 months (95% CI: 18-NA months) for patients who received MPT, 24 months (95% CI: 20-32 months) with MPV and 21.5 months (95% CI: 17-NA months) with MPR, with no significant differences between the three regimens. Among the 69 patients, the overall grade 3-4 hematologic and non-hematologic toxicities were 36% and 43%, respectively. The most common non-hematologic toxicities included all grades of peripheral neuropathy (14% with MPV, 7.2% with MPT and none with MPR), grade 3-4 infections (7.2% with MPV, 4.3% with MPT and 2.9 with MPR) and grade 3-4 cardiovascular disease (4.3% with MPT, 1.4% with MPV and none with MPR). With the use of thromboprophylaxis in all IMID-treated patients, we observed only one deep vein thrombosis in one patient treated with MPT. ConclusionsMPT, MPV and MPR are highly active and well tolerated regimens for previously untreated MM patients. The rates of treatment-associated thrombocytopenia and neutropenia were similar between the 3 different regimens and proved transient, predictable and manageable; few patients required supportive care. The results obtained using MP plus one of the recently developed drugs confirm that MPT, MPV and MPR should be considered the standard of care in the frontline treatment of newly diagnosed transplant-ineligible MM patients. Disclosures:Petrucci:Janssen and Celgene: Honoraria; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

A Randomized Phase 3 Trial Of Melphalan-Lenalidomide-Prednisone (MPR) Or Cyclophosphamide-Prednisone-Lenalidomide (CPR) Vs Lenalidomide Plus Dexamethsone (Rd) In Elderly Newly Diagnosed Multiple Myeloma Patients

BackgroundRd and MPR are effective treatments in newly diagnosed multiple myeloma (NDMM) patients (pts). In this study we compared a non-alkylating containing regimen (Rd) vs alkylating-based regimens (MPR/CPR) in elderly transplant ineligible NDMM pts. MethodsPatients were randomized (2:1) to receive nine 28-day cycles of MPR/CPR or Rd. MPR: lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days; CPR: cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day (eod) in >75 years pts; lenalidomide 25 mg/day for 21 days; prednisone 25 mg every other day. Rd: lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years. After induction, patients were randomized to receive maintenance with lenalidomide alone (10 mg/day for 21 days) or with prednisone (25 mg eod on days 1-28), until disease progression. The primary endpoint was progression-free survival (PFS). ResultsBetween October 2009 and October 2012, 659 pts were enrolled ( MPR/CPR:439 and Rd:220), and 641 pts were evaluable (MPR/CPR:430 and Rd:211). Patient characteristics were well balanced in the 2 groups: median age was 73 years in both groups, 38% of pts were older than 75 years, 27% had ISS stage III in both groups, 21% of patients both in the MPR/CPR and in the Rd groups had unfavorable FISH profile [t(4;14) or t (14;16) or del17p]. After induction, the response rates were similar in the 2 groups: at least PR rate was 75% versus 79% (p=0.52) and CR rate was 9% versus 7% (p=0.35), in the MPR/CPR and Rd group, respectively. No significant difference in response rate were reported between two alkylating containing regimens. After a median follow-up of 21 months, the 2-year PFS was 55% in MPR/CPR and 49% in Rd (HR=0.86, 95% CI: 0.66-1.12, p=0.26), and 2-year OS was 84% in MPR/CPR and 80% in Rd (HR= 0.93, 95% CI: 0.60-1.41, p=0.71)At least one grade ≥3 hematological adverse event was reported in 51% with MPR/CPR and 29% with Rd (p<0.001), with a significant difference between the two alkylating agents (67% MPR and 31% CPR, p<0.001). At least one grade ≥3 extra-hematologic toxicities were similar in the two groups (31% with MPR/CPR and 28% with Rd, p=0.77). with no difference between two alkylating agents (31% both in MPR and CPR group). Second primary malignancies (SPM) were reported in 5 MPR patients (1 hematologic and 4 solid) in 1 CPR patient (hematologic) and in 2 Rd patients (both solid). ConclusionIn a community-based population, triplet alkylating combinations did not lead to different PFS or OS clinical benefits over doublet therapy. Updated results will be presented at the meeting. Disclosures:Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Bringhen:Celgene: Honoraria. Giuliani:Celgene: Research Funding. Cavallo:Celgene: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma

BackgroundLenalidomide has tumoricidal and immunomodulatory activity against multiple myeloma. This double-blind, multicenter, randomized study compared melphalan–prednisone–lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan–prednisone–lenalidomide (MPR) or melphalan–prednisone (MP) followed by placebo in patients 65 years of age or older with newly diagnosed multiple myeloma.MethodsWe randomly assigned patients who were ineligible for transplantation to receive MPR-R (nine 4-week cycles of MPR followed by lenalidomide maintenance therapy until a relapse or disease progression occurred [152 patients]) or to receive MPR (153 patients) or MP (154 patients) without maintenance therapy. The primary end point was progression-free survival.ResultsThe median follow-up period was 30 months. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P<0.001) or MP (13 months; hazard ratio, 0.40; P<0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs. 50% with MP; P<0.001 and P=0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65 to 75 years of age but not in those older than 75 years of age (P=0.001 for treatment-by-age interaction). After induction therapy, a landmark analysis showed a 66% reduction in the rate of progression with MPR-R (hazard ratio for the comparison with MPR, 0.34; P<0.001) that was age-independent. During induction therapy, the most frequent adverse events were hematologic; grade 4 neutropenia was reported in 35%, 32%, and 8% of the patients in the MPR-R, MPR, and MP groups, respectively. The 3-year rate of second primary tumors was 7% with MPR-R, 7% with MPR, and 3% with MP.ConclusionsMPR-R significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age. (Funded by Celgene; MM-015 ClinicalTrials.gov number, NCT00405756.)

Physiological and behavioral adaptation to relocation stress in differentially reared rhesus monkeys: Hair cortisol as a biomarker for anxiety-related responses

Increased hair cortisol concentrations have been associated with stress exposure in both human and nonhuman primates, and hair cortisol is now gaining attention as a biomarker for stress-related health problems. The present study examined the behavioral and physiological reactions of rhesus monkey (Macaca mulatta) infants reared in three different rearing environments to the major stressor of relocation. Infant monkeys (n=61) were studied from birth through 2 years of age. For the first 8 months of life, infants were either with their mothers and peers (MPR, n=21) or reared in a nursery using either peer-rearing (PR, n=20) or surrogate-peer-rearing (SPR, n=20). At approximately 8 months of age, infants were removed from their rearing group, simultaneously placed into a large social environment consisting of infants from all three rearing conditions, and observed for the next 16 months. Behavior was recorded twice per week from 1 to 24 months, and composite anxiety scores were calculated for each monkey. Monkeys were initially shaved at the nape of the neck on day 14 to remove any prenatal effects on hair cortisol deposition. Hair samples were then collected by re-shaving at 6, 12, 18 and 24 months and analyzed for cortisol content. MPR monkeys were the least affected by the stressor, showing smaller increases in anxious behavior than the other groups and more rapid physiological adaptation as assessed using hair cortisol. PR monkeys showed heightened and prolonged anxious behavior, had the highest cortisol levels prior to relocation, and their cortisol levels did not decline until more than a year later. SPR monkeys exhibited more rapid behavioral adaptation than PR monkeys, showing heightened but not prolonged anxious behavior. However, the SPR group showed a marked increase in cortisol in response to the relocation, and like the PR group, their physiological adaptation was slower than that of the MPR group as indicated by elevated cortisol levels at 18 months. By 24 months of age (16 months after relocation), all rearing groups were indistinguishable from one another physiologically and behaviorally. Spearman rank correlation revealed that hair cortisol taken at month 6 was not correlated with composite anxiety scores from months 6 to 8 (just before the relocation), but was positively correlated with composite anxiety scores between months 8 and 12 (immediately after relocation) for PR infants only (r(s)=0.75, p<0.001). Month 6-hair cortisol tended to positively correlate with composite anxiety scores for the following 6 months (months 12-18) for PR monkeys only (r(s)=0.47, p=0.037), which exhibited more anxious behavior than MPR and SPR infants during this period (ANOVA: F((2,60))=14.761, p<0.001) This is the first study to show that elevated hair cortisol early in life is a biomarker for the later development of anxious behavior in response to a major life stressor, particularly for infant monkeys exposed to early life adversity in the form of peer-rearing.

Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) in newly diagnosed multiple myeloma (MM) patients: A phase III trial.

8020 Background: The introduction of novel agents questions the role of autologous stem-cell transplantation (ASCT). This is the first prospective randomized study comparing conventional chemotherapy plus novel agents (MPR) with tandem high-dose melphalan (MEL200) and ASCT in newly diagnosed MM patients (Pts). Methods: All pts (N=402) received four 28-day cycles of lenalidomide (25 mg, d1-21) and low-dose dexamethasone (40 mg, d1,8,15,22) (Rd) as induction. Pts (N=202) were then randomized to MPR [six 28-day cycles of melphalan (0.18 mg/kg d1-4), prednisone (2 mg/kg d1-4) and lenalidomide (10 mg d1-21); pts (N=200)] or MEL200 (tandem melphalan 200 mg/m2 with stem-cell support). Primary end point was PFS. Results: Response rates were similar in the two groups (MPR vs MEL200): ≥ VGPR (60% vs. 58%, p=0.24) and CR (20% vs. 25% p=0.49). After a median follow-up of 20 months, the 18-months PFS was 68% in MPR and 78% in MEL200 (HR=0.58, p=0.006). CR prolonged the 18-months PFS in the MPR (90% vs 66%) and in the MEL200 group (87% vs 76%). The 18-months OS was similar (91% vs 95%; p=0.073). In the MPR and MEL200 groups, G3-4 neutropenia was 55% vs 89% (p <.001); G3-4 infections were 0% vs 17% (p <.001); G3-4 gastrointestinal toxicity was 0% vs. 21% (p<.001); DVT was 2.44% vs 1.13% (p=0.43); second tumors were 0.005% in both arms. Conclusions: MEL200 was superior to MPR for PFS, although toxicities were significantly higher. This is the first report showing a PFS advantage for ASCT in comparison with combinations including novel agents. At present OS is not significantly different in the two groups.