Carfilzomib, thalidomide, and dexamethasone are safe and effective in relapsed and/or refractory multiple myeloma: final report of the single-arm, multicenter, phase II ALLG MM018/AMN002 study.

This multicenter, phase II study of the Australasian Lymphoma and Leukemia Group and the Asian Myeloma Network investigated fixed-duration (18-month) treatment with carfilzomib (K), thalidomide (T), and dexamethasone (d) (KTd) in patients with relapsed and/or refractory multiple myeloma who had received one to three prior lines of therapy. Patients received induction with up to 12 28-day cycles of carfilzomib (20 mg/m2 intravenously in cycle 1 on days 1 and 2, then 56 mg/m2 [36 mg/m2 for patients ≥75 years] from day 8 onwards), thalidomide 100 mg orally in the evening and weekly dexamethasone 40 mg (20 mg for patients ≥75 years). During maintenance, thalidomide was omitted, while carfilzomib was continued on days 1, 2, 15, and 16 with fortnightly dexamethasone. The primary endpoint was progression-free survival. Secondary endpoints were overall response rate, overall survival, duration of response, safety, and tolerability. Ninety-three patients (median age 66.3 years [range, 41.9-84.5]) were enrolled and followed up for a median of 26.4 months (range, 1.6-54.6). The median progression-free survival was 22.3 months (95% confidence interval: 15.7-25.6) and the 2-year progression-free survival was 46.3% (95% confidence interval: 35.1-52.8). The median overall survival was not reached and the 2-year overall survival was 73.8% (95% confidence interval: 62.9-81.9). The overall response rate was 88% (73% had a very good partial response or better). There was no difference in the depth of response, progression-free survival or overall survival comparing Asian and non-Asian cohorts (P=0.61). The safety profile of KTd was consistent with that of each individual drug. KTd is well tolerated and effective in patients with relapsed and/or refractory multiple myeloma irrespective of Asian or non-Asian ethnicity and provides an alternative treatment option, particularly in circumstances in which the use of carfilzomib, lenalidomide, and dexamethasone (KRd) is limited by access, cost, or renal impairment.

Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: Results of the multicenter KMMWP2201 study.

Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed at investigating this regimen's efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age: 63 years). The overall response rate was 90% in responseevaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, highrisk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2 to 3 months prior to start of KRd treatment significantly decreased PFS and overall survival (OS) in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e.delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AEs) were observed in 56% of the patients, and non-fatal or fatal AE's that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.

Efficacy of natural killer cell therapy combined with chemoradiotherapy in murine models of head and neck squamous cell carcinoma.

BACKGROUND AIMS: Natural killer (NK) cell-based cancer immunotherapy is effective when combined with other treatment modalities such as irradiation and chemotherapy. NK cell's antitumor function to treat solid tumor, including head and neck squamous cell carcinoma (HNSCC), has been targeted recently. This study assessed NK cell recruitment in response to chemoradiation therapy (CRT) in HNSCC. METHODS: Ex vivo expansion of NK cell, flow cytometry, cell viability assay, cytotoxicity assay, immunohistochemistry, and animal model were performed. RESULTS: Mouse NK cells were recruited to the tumor site by CRT in a nude mouse model. Furthermore, expanded and activated human NK cells (eNKs) were recruited to the tumor site in response to CRT, and CRT enhanced the anti-tumor activity of eNK in an NOD/SCID IL-2Rγnull mouse model. Various HNSCC cancer cell lines exhibited different NK cell ligand activation patterns in response to CRT that correlated with NK cell-mediated cytotoxicity. CONCLUSIONS: Identifying the activation patterns of NK cell ligands during CRT might improve patient selection for adjuvant NK cell immunotherapy combined with CRT. This is the first study to investigate the NK cell's antitumor function and recruitment with CRT in HNSCC mouse model.

Real-world outcome of patients with extensively pretreated multiple myeloma who were treated with selinexor and dexamethasone: a Korean multicenter retrospective analysis.

The outcomes of patients with myeloma after exposed to penta-classes are extremely poor. Selinexor is the first approved exportin inhibitor for those patients, but intractable toxicities may limit its use. This retrospective study evaluated the real-world efficacy and safety of selinexor plus dexamethasone (XD) and involved 48 patients with multiple myeloma, who were treated from November 2020 to October 2022. Their median age was 64 years, and the median number of prior lines of therapy was 6. The overall response rate was 25%, and the median progression-free survival (PFS) was 2.1 months (95% confidence interval (CI), 1.7-2.5). Patients on a reduced initial dose, delayed treatment, and dose reduction had better PFS. After XD treatment failure, 17 patients received subsequent therapy and had a median PFS of 2.4 months. The median overall survival was 4.6 months (95% CI, 2.3-6.9). Among the patients, 12 (25%) and 17 (35%) experienced dose reduction and delayed treatment, respectively. Our data show that the real-world efficacy of XD treatment in heavily pretreated patients was modest and that improving treatment adherence through reducing initial doses or delaying treatments may improve patient outcomes.

The establishment of a multiple myeloma clinical registry in the Asia-Pacific region: The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR).

BACKGROUND: Multiple myeloma (MM) is the second most common haematological cancer worldwide. Along with related diseases including monoclonal gammopathy of undetermined significance (MGUS), plasma cell leukaemia (PCL) and plasmacytoma, MM incidence is rising, yet it remains incurable and represents a significant disease burden. Clinical registries can provide important information on management and outcomes, and are vital platforms for clinical trials and other research. The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR) was developed to monitor and explore variation in epidemiology, treatment regimens and their impact on clinical outcomes across this region. Here we describe the registry's design and development, initial data, progress and future plans. METHODS: The APAC MRDR was established in 2018 as a multicentre collaboration across the Asia-Pacific, collecting prospective data on patients newly diagnosed with MM, MGUS, PCL and plasmacytoma in Korea, Singapore, Malaysia and Taiwan, with China recently joining. Development of the registry required a multidisciplinary team of clinicians, researchers, legal and information technology support, and financial resources, as well as local clinical context from key opinion leaders in the APAC region. Written informed consent is obtained and data are routinely collected throughout treatment by hospital staff. Data are stored securely, meeting all local privacy and ethics requirements. Data were collected from October 2018 to March 2024. RESULTS: Over 1700 patients from 24 hospitals have been enrolled onto the APAC MRDR to date, with the majority (86%) being newly diagnosed with MM. Bortezomib with an immunomodulatory drug was most frequently used in first-line MM therapy, and lenalidomide-based therapy was most common in second-line. Establishment and implementation challenges include regulatory and a range of operational issues. CONCLUSION: The APAC MRDR is providing 'real-world' data to participating sites, clinicians and policy-makers to explore factors influencing outcomes and survival, and to support high quality studies. It is already a valuable resource that will continue to grow and support research and clinical collaboration in MM and related diseases across the APAC region.

Comparing Ruminative and Distracting Responses and Emotion Regulation Difficulties in Early Community Adolescents With and Without Self-Harm.

Objectives: This study aimed to compare the demographic characteristics, responses to negative emotions, and difficulties in emotion regulation between self-harming adolescents and control individuals aged 12-14 years from the community. Methods: Data were collected from adolescents in Chungcheong Province, South Korea, between September 2021 and November 2022. Demographic characteristics and responses to the Depressed Mood Questionnaire and Difficulties in Emotion Regulation Scale-16 (DERS-16) were compared between the self-harm and control groups. Results: The self-harm group exhibited a higher prevalence of child abuse (odds ratio [OR]=4.787, 95% confidence interval [CI]=1.591-14.409, p=0.005) and school bullying victimization (OR=4.495, 95% CI=2.353-8.588, p<0.001) than those in the control group. The selfharm group displayed higher levels of rumination (t=7.88, p<0.001) and reduced distraction responses (reverse score t=2.25, p=0.025) than those of the control group. Additionally, the self-harm group scored higher on all subscales and the total DERS-16 score (t=7.61, p<0.001). Conclusion: Interventions for self-harming adolescents should address child abuse and bullying victimization. Prevention programs for self-harming adolescents should focus on reducing rumination responses, increasing distractive responses, and addressing difficulties in emotion regulation using dialectical behavior therapy-skill training.

Prognostic analysis according to European LeukemiaNet 2022 risk stratification for elderly patients with acute myeloid leukemia treated with decitabine.

OBJECTIVES: This study aimed to evaluate the prognostic significance of the revised European LeukemiaNet (ELN)-2022 risk stratification model for 123 elderly acute myeloid leukemia (AML) patients treated with decitabine chemotherapy. RESULTS: Based on the ELN-2022 risk stratification, 15 (12.2%), 51 (41.5%), and 57 (46.3%) patients were classified as having favorable, intermediate, and high-risk AML, respectively. In comparison with the ELN-2017 risk stratification, the ELN-2022 risk stratification re-assigned 26 (21.1%) and three (2.4%) patients to the adverse and favorable risk groups, respectively. Survival analysis revealed distinctive overall survival (OS) outcomes among the ELN-2022 risk groups (6-month OS rate: 73.3%, 52.9%, and 47.7% for favorable, intermediate, and adverse risk, respectively; P = 0.101), with a parallel trend observed in the event-free survival (EFS) (6-month EFS rate: 73.3%, 52.9%, and 45.6% for favorable, intermediate, and adverse risk, respectively; P = 0.049). Notably, both OS and EFS in the favorable risk group were significantly superior in comparison to that of the adverse risk group (OS: P = 0.040, EFS: P = 0.030). Although the ELN-2022 C-index (0.559) was greater than the ELN-2017 C-index (0.539), the result was not statistically significant (P = 0.059). Based on the event net reclassification index, we consistently observed significant improvements in the ELN-2022 risk stratification for overall survival (0.21 at 6 months). CONCLUSION: In conclusion, the revised ELN-2022 risk stratification model may have improved the risk classification of elderly AML patients treated with hypomethylating agents compared to the ELN-2017 risk stratification model.

Exploring cellular immunotherapy platforms in multiple myeloma.

Despite major advances in therapeutic platforms, most patients with multiple myeloma (MM) eventually relapse and succumb to the disease. Among the novel therapeutic options developed over the past decade, genetically engineered T cells have a great deal of potential. Cellular immunotherapies, including chimeric antigen receptor (CAR) T cells, are rapidly becoming an effective therapeutic modality for MM. Marrow-infiltrating lymphocytes (MILs) derived from the bone marrow of patients with MM are a novel source of T cells for adoptive T-cell therapy, which robustly and specifically target myeloma cells. In this review, we examine the recent innovations in cellular immunotherapies, including the use of dendritic cells, and cellular tools based on MILs, natural killer (NK) cells, and CAR T cells, which hold promise for improving the efficacy and/or reducing the toxicity of treatment in patients with MM.

Prognostic Significance Of Sequential 18f-fdg Pet/Ct During Frontline Treatment Of Peripheral T Cell Lymphomas.

BACKGROUND/AIMS: The prognostic significance of 18F-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET/CT) in peripheral T-cell lymphomas (PTCLs) are controversial. We explored the prognostic impact of sequential 18F-FDG PET/CT during frontline chemotherapy of patients with PTCLs. METHODS: In total, 143 patients with newly diagnosed PTCLs were included. Sequential 18F-FDG PET/CTs were performed at the time of diagnosis, during chemotherapy, and at the end of chemotherapy. The baseline total metabolic tumor volume (TMTV) was calculated using the the standard uptake value with a threshold method of 2.5. RESULTS: A baseline TMTV of 457.0 cm3 was used to categorize patients into high and low TMTV groups. Patients with a requirehigh TMTV had shorter progression-free survival (PFS) and overall survival (OS) than those with a low TMTV (PFS, 9.8 vs. 26.5 mo, p = 0.043; OS, 18.9 vs. 71.2 mo, p = 0.004). The interim 18F-FDG PET/CT response score was recorded as 1, 2-3, and 4-5 according to the Deauville criteria. The PFS and OS showed significant differences according to the interim 18F-FDG PET/CT response score (PFS, 120.7 vs. 34.1 vs. 5.1 mo, p < 0.001; OS, not reached vs. 61.1 mo vs. 12.1 mo, p < 0.001). CONCLUSION: The interim PET/CT response based on visual assessment predicts disease progression and survival outcome in PTCLs. A high baseline TMTV is associated with a poor response to anthracycline-based chemotherapy in PTCLs. However, TMTV was not an independent predictor for PFS in the multivariate analysis.

Nation-Wide Retrospective Analysis of Allogeneic Stem Cell Transplantation in Patients with Multiple Myeloma: A Study from Korean Multiple Myeloma Working Party (KMM1913).

PURPOSE: The role of allogeneic stem cell transplantation (alloSCT) in multiple myeloma (MM) treatment remains controversial. We conducted a retrospective, multicenter, nationwide study in Korea to evaluate the outcomes of alloSCT in Asian patients with MM. MATERIALS AND METHODS: Overall, 109 patients with MM who underwent alloSCT between 2003 and 2020 were included in this study. Data were collected from the Korean Multiple Myeloma Working Party Registry. RESULTS: The overall response rate and stringent complete response plus complete response (CR) rates were 67.0 and 46.8%, respectively, after alloSCT. At a median follow-up of 32.5 months, the 3-year probability of progression-free survival (PFS) and overall survival (OS) rates were 69.3% and 71.8%, respectively. The 3-year probabilities of OS rates in the upfront alloSCT, tandem auto-alloSCT, and later alloSCT groups were 75.0%, 88.9%, and 61.1%, respectively. Patients who achieved CR before or after alloSCT had significantly longer OS (89.8 vs. 18 months and 89.8 vs. 15.2 months, respectively). Even though patients who did not achieve CR prior to alloSCT, those who achieve CR after alloSCT had improved PFS and OS compared to those who had no achievement of CR both prior and after alloSCT. Patients who underwent alloSCT with 1-2 prior treatment lines had improved PFS (22.4 vs. 4.5 months) and OS (45.6 vs. 15.3 months) compared to those with three or more prior treatment lines. CONCLUSION: AlloSCT may be a promising therapeutic option especially for younger, chemosensitive patients with earlier implementation from relapse.

Validation of the 2022 European LeukemiaNet risk stratification for acute myeloid leukemia.

This study aimed to validate the 2022 European LeukemiaNet (ELN) risk stratification for acute myeloid leukemia (AML). A total of 624 newly diagnosed AML patients from 1998 to 2014 were included in the analysis. Genetic profiling was conducted using targeted deep sequencing of 45 genes based on recurrent driver mutations. In total, 134 (21.5%) patients had their risk classification reassessed according to the 2022 ELN risk stratification. Among those initially classified as having a favorable risk in 2017 (n = 218), 31 and 3 patients were reclassified as having intermediate risk or adverse risk, respectively. Among the three subgroups, the 2022 ELN favorable-risk group showed significantly longer survival outcomes than the other groups. Within the 2017 ELN intermediate-risk group (n = 298), 21 and 46 patients were reclassified as having favorable risk or adverse risk, respectively, and each group showed significant stratifications in survival outcomes. Some patients initially classified as having adverse risk in 2017 were reclassified into the intermediate-risk group (33 of 108 patients), but no prognostic improvements were observed in this group. A multivariable analysis identified the 2022 ELN risk stratification, age, and receiving allogeneic hematopoietic cell transplantation as significant prognostic factors for survival. The 2022 ELN risk stratification enables more precise decisions for proceeding with allogeneic hematopoietic cell transplantation for AML patients.

Generation of potent cytotoxic T lymphocytes against in male patients with non-muscle invasive bladder cancer by dendritic cells loaded with dying T24 bladder cancer cells

ABSTRACT Background In order to induce a potent cytotoxic T lymphocyte (CTL) response in dendritic cell (DC)-based immunotherapy for bladder cancer, various tumor antigens can be loaded onto DCs. Objective The aim of this study was to establish a method of immunotherapy for male patients with non-muscle invasive bladder cancer (NMIBC), using bladder cancer-specific CTLs generated in vitro by DCs. Materials and Methods Monocyte-derived DCs from bladder cancer patients were induced to mature in a standard cytokine cocktail (IL-1β, TNF-α, IL-6, and PGE2: standard DCs, sDCs) or anα-type 1-polarized DC (αDC1) cocktail (IL-1β, TNF-α, IFN-α, IFN-γ, and polyinosinic:polycytidylic acid) and loaded with the UVB-irradiated bladder cancer cell line, T24. Antigen-loaded αDC1s were evaluated by morphological and functional assays, and the bladder cancer-specific CTL response was analyzed by cytotoxic assay. Results The αDC1s significantly increased the expression of several molecules pertaining to DC maturation, regardless of whether or not the αDC1s were loaded with tumor antigens, relative to sDCs. The αDC1s demonstrated increased production of interleukin-12 both during maturation and after subsequent stimulation with CD40L that was not significantly affected by loading with tumor antigens as compared to that of sDCs. Bladder cancer-specific CTLs targeting autologous bladder cancer cells were successfully induced by αDC1s loaded with dying T24 cells. Conclusion Autologous αDC1s loaded with an allogeneic bladder cancer cell line resulted in increased bladder cancer-specific CTL responses as compared to that with sDCs, and therefore, may provide a novel source of DC-based vaccines that canbe used in immunotherapy for male patients with NMIBC.