Jan Dara The Finale Full Movie Free Download
Agathe Thies
Multiple myeloma (MM) remains largely incurable, despite improvements in survival outcomes in the last decade because of the availability of novel therapeutics, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies.1 Selective treatment pressures lead to clonal expansion and heterogeneity, followed by subsequent resistance to therapy and relapse.2,3 The IMiD lenalidomide is frequently used during front-line induction and maintenance therapy for MM.4 Because lenalidomide is typically administered until disease progression, patients who relapse are often refractory to lenalidomide, creating a need for lenalidomide-sparing treatment options for relapsed/refractory (RR) MM.5
CANDOR, a phase 3, randomized, open-label trial comparing KdD with Kd in patients with RRMM recruited 466 patients from 102 international sites. A detailed description of the CANDOR study design has been previously published.10,11
All patients provided written informed consent, and the study protocol was approved by institutional review boards or independent ethics committees at all participating institutions. X.S. and C.L. analyzed the data, and all authors had access to the primary clinical trial data. CANDOR is registered at www.clinicaltrials.gov as #NCT03158688.
PFS was defined as the time from randomization until confirmed disease progression or death due to any cause, whichever occurred first. Disease progression was centrally assessed every 28 7 days based on the IMWG uniform response criteria using a validated Onyx Response Computer Algorithm in a blinded manner by the sponsor.
Adverse events (AEs) were collected up to 30 days after the last dose of any study treatment or at end of study, whichever occurred first. AEs were graded per the National Cancer Institute Common Terminology Criteria for AEs (version 4.03).13 All patients with treatment-related and serious AEs were followed up until the AEs were stabilized or resolved.
A sensitivity analysis for OS was performed using the inverse probability of censoring weights method, which provides an unbiased estimate of treatment effect if all baseline and time-dependent prognostic factors are measured and available (no unmeasured confounders assumption).14 A predictive model was built for the probability of each patient remaining nonswitching until a certain timepoint and then weighed at each time point per the inverse probability of nonswitching during each prespecified time interval. In the adjusted analysis, higher weights were assigned to non-switching patients with characteristics similar to the switching patients. After weights were calculated, a weighted Cox stratified model was used to estimate the adjusted HR for treatment effect.
The post hoc analysis of derived time to subsequent progression or death (dPFS2) was defined as the time from randomization to dPFS2, whichever occurred first. Because the date of subsequent disease progression was not collected in the CANDOR study, dPFS2 was assessed using an algorithm that found time from randomization to start of next treatment. If a patient had disease progression on CANDOR therapy, the start date of next line of therapy was used; if a patient stopped receiving KdD or Kd for reason other than progressive disease, the start date of the third line of therapy was used. Death in follow-up was also considered a surrogate for progressive disease when calculating dPFS2. Comparison of dPFS2 among treatment arms was conducted using stratified log-rank test.
Safety analyses used the safety population, which included all patients receiving a dose of study treatment. Exposure-adjusted analyses of treatment-emergent AEs (TEAEs) and fatal TEAEs were performed post hoc to clarify differences in treatment duration.
Patients were considered refractory to a drug received in previous regimens if any of the following criteria were met: best response to any regimen containing the drug was stable disease or progressive disease; reason for which the drug was stopped was progression in any regimen; and date of relapse or progression was after start date and within 60 days after stop date of the drug in any regimen.
After a median follow-up of >50 months, the median OS was 50.8 months (95% CI, 44.7 to not estimable [NE]) in the KdD arm vs 43.6 (95% CI, 35.3 to NE) months in the Kd arm, with an HR of 0.78 (95% CI, 0.60-1.03; Figure 2). Although there is a 7.2-month numerical difference in OS in favor of KdD, the 1-sided P-value of .0417 did not meet the prespecified statistical significance level of .021 (1-sided). These results were generally consistent across 4 prespecified OS sensitivity analyses (supplemental Table 2). Prespecified subgroup analyses showed an OS improvement trend with KdD vs Kd in most subgroups, including patients with lenalidomide-exposed, lenalidomide-refractory, PI-exposed, or PI-refractory disease. The greatest OS benefit of KdD was seen in patients with high-risk cytogenetics (HR, 0.52 [0.29-0.94]) and in patients with international staging system stage III at screening (HR, 0.58 [0.35-0.99]; Figure 3).
In previously published RRMM studies, such as ASPIRE, ENDEAVOR, CASTOR, and POLLUX,17-20 a statistically significant improvement in OS was observed in an era when subsequent lines of therapies did not include highly effective novel agents. However, the confounding effect of potent therapies after progression and the prolonged follow-up required have hindered the utility of using OS as an end point in recent years.21 Improved myeloma therapies over the last decade have resulted in median survival approaching 10 years,22 resulting in a steady approval of new therapies that will be available before the end point is met.23
Because many patients with RRMM are lenalidomide refractory, there is a strong need for lenalidomide-sparing treatments, such as KdD. The KdD triplet maintains strong efficacy in patients who are refractory to lenalidomide, with improved PFS (HR, 0.59)11 and OS (HR, 0.69) compared with Kd. Similar trends in OS benefit were observed in subgroups with prior PI, lenalidomide exposure, or high-risk cytogenetics.
Although discontinuation of any study treatment or carfilzomib treatment because of TEAEs occurred slightly more frequently in patients treated with KdD vs Kd, discontinuation of carfilzomib or daratumumab because of TEAEs decreased over time in both groups, suggesting no cumulative toxicity. Infections continued to be 1 of the most common AEs in patients in both the KdD and Kd arms, including respiratory tract infections and pneumonia. In keeping with the known safety profile of anti-CD38 monoclonal antibodies,30,31 there were higher rates of neutropenia and infections in the KdD arm; however, differences in rates of fatal infection were attenuated when adjusted for exposure. Rates of upper respiratory tract infection and pneumonia were similar in the IKEMA study (upper respiratory tract infection [Isa-Kd, 36%; Kd, 24%] and pneumonia [Isa-Kd, 29%; Kd, 23%]).32 Close monitoring and timely management of infections are appropriate for patients at high risk for complications.
Contribution: S.Z.U., H.Q., M.-V.M., O.L., X.L., D.S., K.W., and M.D. collected the data; S.Z.U., H.Q., M.-V.M., O.L., X.L., D.S., K.W., X.S., C.L., and M.D. were involved in study conceptualization and design, data analysis and interpretation, and manuscript writing; and all authors gave the final approval of the manuscript and are accountable for all aspects of the work.
Conflict-of-interest disclosure: S.Z.U. reports grants and personal fees from AbbVie, Amgen, Bristol Myers Squibb (BMS), Celgene, GlaxoSmithKline (GSK), Janssen, Merck, MundiPharma, Oncopeptides, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda. H.Q. reports grants from Amgen, Celgene, GSK, and Karyopharm; consultancy and/or membership on an advisory committee from BMS, Celgene, GSK, Janssen, Karyopharm, and Takeda; receipt of study materials from Amgen, GSK, Karyopharm, and Sanofi; and leadership or fiduciary role with Amgen, BMS, and GSK. M.-V.M. reports consulting fees from Janssen, Celgene, Amgen, Takeda, AbbVie, GSK, Oncopeptides, Adaptive, Sanofi, Pfizer, Roche, and Bluebird Bio. O.L. reports honoraria and/or membership on the board of directors for Adaptive, Amgen, Celgene, Janssen, and Takeda, and membership on independent data monitoring committees for Merck and Theradex. X.L. reports honoraria from Sanofi, Takeda, Oncopeptides, Karyopharm, Amgen, Carsgen, Incyte, Novartis, Celgene, Janssen, BMS, Merck, GSK, and AbbVie. D.S. reports honoraria from and service on speakers bureaus for Novartis, Karyopharm, Janssen, BMS, Takeda, Amgen, and Celgene; consulting and membership on the boards of directors or advisory committees for Janssen, BMS, Takeda, Amgen, Celgene, and Celularity Scientific; and research funding from Janssen, BMS, Takeda, Amgen, and Celgene. K.W. reports consultancy for Janssen, Adaptive Biotech, Amgen, BMS, Sanofi, Takeda, Oncopeptides, Karyopharm, GSK, and Celgege; honoraria from Janssen, Adaptive Biotech, Amgen, BMS, Celgene, Sanofi, Takeda, and GSK; and research funding from Janssen, Amgen, Celgene, and Sanofi. X.S. reports employment with Parexel International. C.L. reports employment with and stockholdings in Amgen. M.D. reports consulting fees from Janssen, Amgen, BMS, Takeda, and BeiGene; honoraria from BeiGene, Janssen, Amgen, BMS, Takeda; and research funding from BMS, Janssen, Amgen, Takeda, and BeiGene.
Chakraborty concludes her Daevabad trilogy with such emotional anguish that readers will come away needing time to mourn the loss of such a great series and time to process the events taken place. As Nahri, Dara, and Ali must face the consequences for the actions of their family members and for their own actions, war breaks out around them, promising death and heartbreak for both sides. I truly enjoyed this finale to the series, even though having to say goodbye to these beloved characters left me feeling empty and wanting more.
7fc3f7cf58