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.

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 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.

Risk stratification for early mortality in newly diagnosed acute promyelocytic leukemia: a multicenter, non-selected, retrospective cohort study.

Introduction: Despite the current effective treatments for acute promyelocytic leukemia (APL), early mortality (EM), defined as death within 30 days of presentation, is a major hurdle to long-term survival. Methods: We performed a multicenter retrospective study to evaluate the incidence and clinical characteristics of EM in patients with newly diagnosed APL and to develop a risk stratification model to predict EM. Results: We identified 313 eligible patients diagnosed between 2000 and 2021 from five academic hospitals. The median age was 50 years (range 19-94), and 250 (79.9%) patients were <65 years. Most patients (n=274, 87.5%) received their first dose of all-trans retinoic acid (ATRA) within 24 hours of presentation. EM occurred in 41 patients, with a cumulative incidence of 13.1%. The most common cause of EM was intracranial hemorrhage (n=22, 53.6%), and most EMs (31/41, 75.6%) occurred within the first seven days of APL presentation. In a multivariable analysis, we identified three independent factors predicting EM: age ≥65 years (HR, 2.56), white blood cell count ≥8.0 x 109/L (HR, 3.30), and ATRA administration >24 hours of presentation (HR, 2.95). Based on these factors, patients were stratified into three categories with a significantly increasing risk of EM: 4.1% for low risk (54.3%; no risk factors; HR 1), 18.5% for intermediate risk (34.5%; 1 factor; HR 4.81), and 40.5% for high risk (11.2%; 2-3 factors; HR 13.16). Discussion: The risk of EM is still not negligible in this era of ATRA-based therapies. Our risk model serves as a clinically useful tool to identify high-risk patients for EM who may be candidates for novel treatments and aggressive supportive strategies.

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.

Long-Term Efficacy and Safety of Eculizumab in Patients With Paroxysmal Nocturnal Hemoglobinuria and High Disease Burden: Real-World Data From Korea.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by uncontrolled terminal complement activation. Eculizumab, a monoclonal antibody C5 inhibitor was introduced in Korea in 2009 and has been the standard treatment option for PNH. METHODS: This study assessed the long-term efficacy/safety of eculizumab in PNH using real-world data from the Korean Health Insurance Review and Assessment Service. Eighty patients who initiated eculizumab from 2009-2020 were enrolled. RESULTS: At eculizumab initiation, the median age was 51.5 years, lactate dehydrogenase (LDH) 6.8 × upper limit of normal, and granulocyte clone size 93.0%. All patients had at least one PNH-related complication before eculizumab initiation, including renal failure (n = 36), smooth muscle spasm (n = 24), thromboembolism (n = 20), and pulmonary hypertension (n = 15). The median (range) duration of eculizumab treatment was 52.7 (1.0, 127.3) months (338.6 total treated patient-years). Despite high disease activity in the study population before treatment initiation, overall survival was 96.2% and LDH levels were stabilized in most patients during treatment. PNH-related complications at treatment initiation were resolved in 44.4% of patients with renal failure, 95.8% with smooth muscle spasm, 70.0% with thromboembolism, and 26.7% with pulmonary hypertension. Extravascular hemolysis occurred in 28.8% of patients (n = 23; 0.09 per patient-year) and breakthrough hemolysis in 18.8% (n = 15; 0.06 per patient-year). No treatment discontinuation cases related to eculizumab were observed. CONCLUSION: These data provided evidence for the long-term efficacy and safety of eculizumab in Korean PNH patients with high disease burdens.

The prognostic impact of reduced variant burden in elderly patients with acute myeloid leukemia treated with decitabine.

BACKGROUND/AIMS: We evaluated the role of next-generation sequencing (NGS)-based disease monitoring for elderly patients diagnosed with acute myeloid leukemia (AML) who received decitabine therapy. METHODS: A total of 123 patients aged > 65 years with AML who received decitabine were eligible. We analyzed the dynamics of variant allele frequency (VAF) in 49 available follow-up samples after the fourth cycle of decitabine. The 58.6% VAF clearance (Δ, [VAF at diagnosis - VAF at follow-up] × 100 / VAF at diagnosis) was the optimal cut-off for predicting overall survival (OS). RESULTS: The overall response rate was 34.1% (eight patients with complete remission [CR], six of CR with incomplete hematologic recovery, 22 with partial responses, and six with morphologic leukemia-free status). Responders (n = 42) had significantly better OS compared with non-responders (n = 42) (median, 15.3 months vs. 6.5 months; p < 0.001). Of the 49 patients available for follow-up targeted NGS analysis, 44 had trackable gene mutations. The median OS of patients with ΔVAF ≥ 58.6% (n=24) was significantly better than that of patients with ΔVAF < 58.6% (n = 19) (20.5 months vs. 9.8 months, p = 0.010). Moreover, responders with ΔVAF ≥ 58.6% (n = 20) had a significantly longer median OS compared with responders with VAF < 58.6% (n = 11) (22.5 months vs. 9.8 months, p = 0.004). CONCLUSION: This study suggested that combining ΔVAF ≥ 58.6%, a molecular response, with morphologic and hematologic responses can more accurately predict OS in elderly AML patients after decitabine therapy.

Clinical Significance of bZIP In-Frame CEBPA-Mutated Normal Karyotype Acute Myeloid Leukemia.

PURPOSE: We evaluated the characteristics of CCAAT/enhancer-binding protein α (CEBPA) mutations and the significance of a basic leucine zipper in-frame mutation (bZIPin-f) of CEBPA in patients with acute myeloid leukemia with a normal karyotype. Materials and Methods: Based on updated knowledge of CEBPA mutations, we conducted next-generation sequencing analyses in a previously established real-world cohort. RESULTS: Among 78 of a total of 395 patients (19.7%), 50 had bZIPin-f CEBPA, and 28 had non-bZIPin-f CEBPA. In the multivariate analysis, patients with NPM1mut, those with bZIPin-f CEBPA, and those who underwent allogeneic hematopoietic cell transplantation (allo-HCT) had favorable overall survival (OS), but FLT3-ITDmut was a poor prognostic indicator. For relapse-free survival (RFS) and cumulative incidence of relapse, bZIPin-f CEBPA, and allo-HCT were associated with favorable outcomes; FLT3-ITDpos was associated with worse outcomes. In the CEBPA double-mutated group (CEBPAdm), bZIPin-f CEBPA was associated with superior outcomes in terms of OS (p=0.007) and RFS (p=0.007) compared with non-bZIPin-f CEBPA. Of 50 patients with bZIPin-f CEBPA, 36 patients had at least one mutation. When grouped by the presence of mutations in chromatic/DNA modifiers (C), cohesion complex (C), and splicing genes (S) (CCS mutations), CCS-mutated bZIPin-f CEBPA was associated with poor OS (p=0.044; hazard ratio [HR], 2.419) and a trend in inferior RFS (p=0.186; HR, 1.838). CONCLUSION: Only bZIPin-f CEBPA was associated with favorable outcomes in patients with CEBPAdm. However, some mutations accompanying bZIPin-f CEBPA showed inferior OS; thus, further studies with larger numbers of patients are required for clear conclusions of the significance of bZIPin-f CEBPA.

Expanded natural killer cells potentiate the antimyeloma activity of daratumumab, lenalidomide, and dexamethasone in a myeloma xenograft model.

The development of new treatment agents in recent decades has significantly improved the survival of patients with multiple myeloma (MM). Nonetheless, MM remains an incurable disease; therefore, novel combination therapies are required. Natural killer (NK) cells are one of the safest immunotherapeutic options. In this study, we found that the anti-myeloma activity of expanded NK cells (eNKs) was improved by daratumumab, lenalidomide, and dexamethasone (DRd) in an MM xenograft mouse model. NK cells expanded from peripheral blood mononuclear cells collected from MM patients were highly cytotoxic against DRd pretreated tumor cells in vitro. To mimic the clinical protocol, a human MM xenograft model was developed using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγnull (NSG) mice. MM bearing mice were randomly divided into six groups: no treatment, eNK, Rd, Rd + eNKs, DRd, and DRd + eNKs. DRd significantly enhanced the cytotoxicity of eNKs by upregulating NK cell activation ligands and effector function. DRd in combination with eNKs significantly reduced the serum M-protein level and prolonged mouse survival. In addition, DRd significantly increased the persistence of eNK and homing to MM sites. These results show that the anti-myeloma activity of ex vivo-expanded and activated NK cells is augmented by the immunomodulatory effect of DRd in MM-bearing mice, suggesting the therapeutic potential of this combination for MM patients.

Next-generation sequencing-based analysis to assess the pattern of relapse in patients with Philadelphia-positive acute lymphoblastic leukemia.

In this study, we performed serial monitoring using targeted DNA sequencing to identify genetic alterations in adults with Philadelphia-positive acute lymphoblastic leukemia (Ph-ALL). Deep sequencing was performed by targeting the coding regions of 45 genes with recurrent driver mutations and 1129 single nucleotide polymorphism sites. Of the 43 patients that we examined, at least one case of genetic alterations was detected in 38 (88%) of the 43 patients at diagnosis (somatic mutations in 10 patients [23%] and copy number aberrations [CNA] in 36 patients [84%]). The most frequently detected CNA lesions were in IKZF1 (n = 25, 58%) and the most frequently mutated gene was SETD2 (n = 5). At least one genetic abnormality (loss, gain, or persistence) was observed in all the samples obtained at relapse that were available for analysis (n = 15), compared with the samples obtained at diagnosis (disappearance of any previously detected genetic alterations: 11 patients [73%]; new genetic abnormalities: nine patients [60%]; and persistent genetic abnormalities: eight patients [53%]]. The most frequently deleted lesions were in IKZF1 (n = 9, 60%), and the most frequently mutated gene was ABL1 (eight patients, 53%). Our data indicate that leukemic progression may be associated with complex genetic alterations in Ph-ALL during the course of treatment.

Allogeneic hematopoietic cell transplantation can overcome the adverse prognosis indicated by secondary-type mutations in de novo acute myeloid leukemia.

Secondary-type mutations (STMs), namely SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2, are more frequently detected in secondary acute myeloid leukemia (AML) than in de novo AML. Whether de novo AML with STMs should be differently managed is, however, unclear. In 394 patients diagnosed with de novo AML who had a normal karyotype, the genetic profiling via targeted deep sequencing of 45 genes revealed 59 patients carrying STMs (STM+). The STM+ group showed shorter overall survival (OS) than the STM- group (5-year OS, 15.3 vs. 31.0%) (hazard ratio [HR]: 1.975, 95% confidence interval [CI]: 1.446-2.699, p < 0.001). Among the 40 STM+ patients who achieved CR, those who received allogeneic HCT (n = 15) showed better OS (5-year OS, 40.0 vs. 12.0%) (HR: 0.423, 95% CI: 0.184-0.975, p = 0.043) and relapse-free survival (5-year, 40.0 vs. 8.0%) (HR: 0.438, 95% CI: 0.189-1.015, p = 0.054) than those who received consolidation chemotherapy only. The cumulative incidence of relapse was lower in the patients who received allogeneic HCT (5-year, 33.3 vs. 60.0%) (HR: 0.288, 95% CI: 0.111-0.746, p = 0.011), and non-relapse mortality was similar between the two groups (p = 0.935). In conclusion, STM is an independent prognostic factor for adverse outcomes in AML that can be overcome by allogeneic HCT.

Safety and efficacy of nilotinib in adult patients with chronic myeloid leukemia: a post-marketing surveillance study in Korea.

Background: Nilotinib is a tyrosine kinase inhibitor approved by the Ministry of Food and Drug Safety for frontline and 2nd line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). This study aimed to confirm the safety and efficacy of nilotinib in routine clinical practice within South Korea. Methods: An open-label, multicenter, single-arm, 12-week observational post-marketing surveillance (PMS) study was conducted on 669 Korean adult patients with Ph+ CML from December 24, 2010, to December 23, 2016. The patients received nilotinib treatment in routine clinical practice settings. Safety was evaluated by all types of adverse events (AEs) during the study period, and efficacy was evaluated by the complete hematological response (CHR) and cytogenetic response. Results: During the study period, AEs occurred in 61.3% (410 patients, 973 events), adverse drug reactions (ADRs) in 40.5% (271/669 patients, 559 events), serious AEs in 4.5% (30 patients, 37 events), and serious ADRs in 0.7% (5 patients, 8 events). Furthermore, unexpected AEs occurred at a rate of 6.9% (46 patients, 55 events) and unexpected ADRs at 1.2% (8 patients, 8 events). As for the efficacy results, CHR was achieved in 89.5% (442/494 patients), and minor cytogenetic response or major cytogenetic response was achieved in 85.8% (139/162 patients). Conclusion: This PMS study shows consistent results in terms of safety and efficacy compared with previous studies. Nilotinib was well tolerated and efficacious in adult Korean patients with Ph+ CML in routine clinical practice settings.

Genetic changes during leukemic transformation to secondary acute myeloid leukemia from myeloproliferative neoplasms.

Leukemic transformation (LT) is the main cause of death for patients with myeloproliferative neoplasms (MPNs). To study genetic changes associated with the LT, we performed targeted sequencing in 26 MPN patients including 21 with paired samples. We observed that, besides three driver genes, IDH2 (19%) and ASXL1 (14%) were also frequently mutated at MPN diagnosis. Although variant allele frequencies (VAFs) of mutations in DNA methylation and spliceosome did not expand during LT, they were enriched in patients with LT (the LT group). At follow-up, we also observed acquisition of mutations, mostly in the LT group. When considering dynamics of VAF from diagnosis to follow-up, VAFs in the LT group expanded (median VAF, 36.7-43.7%, p = 0.045). In contrast, mutations in patients with no clinical progression was stable (median VAF, 36.3-35.7%, p = 0.739). Overall, the present study demonstrates genetic changes during LT and provides the potential for prognostic application.

Novel IL-15 dendritic cells have a potent immunomodulatory effect in immunotherapy of multiple myeloma.

Dendritic cells (DCs) are the most potent antigen-presenting cells, and have thus been used in clinical cancer vaccines. However, the effects of DC vaccines are still limited, leading researchers to explore novel ways to make them effective. In this study, we investigated whether human monocyte-derived DCs generated via the addition of interleukin 15 (IL-15) had a higher capacity to induce antigen-specific T cells compared to conventional DCs. We isolated CD14+ monocytes from peripheral blood from multiple myeloma (MM) patients, and induced immature DCs with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4 in the presence or absence of IL-15 for 4-6 days. Then we generated mature DCs (mDCs) with lipopolysaccharide for another 2 days [IL-15 mDCs (6 days), IL-15 mDCs (8 days), and conventional mDCs (8 days)]. IL-15 mDCs (6 days) showed higher expression of MHC I and II, CD40, CD86, and CCR7, and the secretion of IFN-γ was significantly higher compared to conventional mDCs. IL-15 mDCs (6 days) showed superior polarization of naïve T cells toward Th1 cells and a higher proportion of activated T cells, cytokine-induced killer (CIK) cells, and natural killer (NK) cells for inducing strong cytotoxicity against myeloma cells, and lower proportion of regulatory T cells compared to conventional mDCs. These data imply that novel multipotent mDCs generated by the addition of IL-15, which can be cultivated in 6 days, resulted in outstanding activation of T cells, CIK cells and NK cells, and may facilitate cellular immunotherapy for cancer patients.

Real-world evidence of levofloxacin prophylaxis in elderly patients with newly diagnosed multiple myeloma who received bortezomib, melphalan, and prednisone regimen.

BACKGROUND: Although survival outcomes of multiple myeloma (MM) have improved with the development of new and effective agents, infection remains the major cause of morbidity and mortality. Here, we evaluated the efficacy of levofloxacin prophylaxis (in a real-world setting) during bortezomib, melphalan, and prednisone (VMP) therapy in elderly patients with newly diagnosed MM. METHODS: This study retrospectively analyzed the records of patients with newly diagnosed MM treated with the VMP regimen between February 2011 and September 2020 at three institutes of the Republic of Korea. RESULTS: Of a total of 258 patients, 204 (79.1%) received levofloxacin prophylaxis during VMP therapy. The median number of levofloxacin prophylaxis cycles was 4 (range, 1‒9), but 10 patients did not complete the planned prophylaxis because of side effects. Sixty-six patients (25.5%) experienced severe infections during VMP therapy, most of which (74.7%) occurred within the first four cycles of VMP therapy regardless of levofloxacin prophylaxis status. Early severe infection was significantly associated with poor survival. In multivariate analysis, levofloxacin prophylaxis was significantly associated with a lower risk in early severe infection. CONCLUSION: Our findings suggest that levofloxacin prophylaxis should be considered at least during the first four cycles of VMP therapy in elderly patients with newly diagnosed MM.

Diagnostic Accuracy and Prognostic Relevance of Immunoglobulin Heavy Chain Rearrangement and 18F-FDG-PET/CT Compared With Unilateral Bone Marrow Trephination for Detecting Bone Marrow Involvement in Patients With Diffuse Large B-Cell Lymphoma.

BACKGROUND: In diffuse large B-cell lymphoma (DLBCL), bone marrow involvement (BMI) has an important clinical implication as a component of staging and International Prognostic Index. This study aimed to determine whether molecular analysis of immunoglobulin heavy chain (IgH) genes and positron emission tomography-computed tomography (PET/CT) could overcome the limitation of defining morphologic BMI by trephination biopsy and could increase the diagnostic accuracy or prognostic prediction. METHODS: A total of 94 de novo patients with DLBCL underwent PET/CT, polymerase chain reaction (PCR) test for detection of IgH gene rearrangement, and unilateral bone marrow (BM) trephination at diagnosis. RESULTS: A total of 9 patients (9.6%) were confirmed to present morphologic BMI (mBMI) based on trephination biopsy. On the other hand, 21 patients (22.3%) were confirmed to have IgH clonality (IgH BMI), while 16 (17.0%) were classified with BMI based on the assessment of PET/CT (PET BMI). Each IgH rearrangement PCR and PET/CT showed the high negative predictive value of detecting the BMI. However, the combined assessment of IgH rearrangement and PET/CT could increase the diagnostic accuracy and specificity with 87.2% and 97.0%, respectively. The survival outcome of patients with double positive PET BMI and IgH BMI was significantly worse than that with either single positive PET BMI or IgH BMI, and even less than patients with neither PET BMI nor IgH BMI (3-year PFS: 50.0% vs. 75.4% vs. 97.9%, P = 0.007, 3-year OS: 50.0% vs. 75.6% vs. 80.1%, P = 0.035, respectively). CONCLUSION: This study suggests that the combined evaluation of PET/CT and IgH rearrangement could give additional information for predicting therapeutic outcomes in patients with negative morphologic BMI as an important part of the prognosis.

Favorable Long-Term Outcomes with Autologous Stem Cell Transplantation for High-Risk Multiple Myeloma Patients with a Positive Result On 18F-FDG PET/CT at Baseline.

BACKGROUND: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is a useful tool for identifying high-risk features in patients with newly diagnosed multiple myeloma (NDMM). This study evaluated the role of autologous stem cell transplantation (ASCT) in patients presenting with positive results on PET/CT scans. MATERIALS AND METHODS: The medical records of 210 patients who underwent PET/CT at diagnosis were retrospectively reviewed. Eligible patients for transplantation proceeded to upfront ASCT with high-dose chemotherapy (HDT) after induction therapy with novel agents. RESULTS: The presence of a number of focal lesions (FL) >3 and extramedullary disease (EMD) occurred in 111 and 35 patients, respectively. ASCT was performed in 54 patients. Among patients with FL > 3, those treated with ASCT showed a prolonged 2-year progression-free survival (PFS) and overall survival (OS) rates compared to those not treated with ASCT (PFS, 60.2% vs. 23.5%, P < 0.001; OS, 91.7% vs. 63.6%, P = 0.005). In patients with FL ≤ 3, treatment by ASCT was associated with a higher 2-year PFS rate than no treatment by ASCT (74.0% vs. 54.9%, P = 0.040). The OS of patients treated with ASCT was not significantly longer than that of patients not treated with ASCT (P = 0.115). In multivariate analysis, FL > 3, Revised International Staging System (R-ISS), and upfront ASCT were independent prognostic factors for PFS and OS. CONCLUSION: Presenting FL > 3 on baseline PET/CT represents a high-risk feature in patients with NDMM. Frontline ASCT with HDT prolonged the survival of patients with FL > 3.

Expansion of cytotoxic natural killer cells in multiple myeloma patients using K562 cells expressing OX40 ligand and membrane-bound IL-18 and IL-21.

BACKGROUND: Natural killer (NK) cell-based immunotherapy is a promising treatment approach for multiple myeloma (MM), but obtaining a sufficient number of activated NK cells remains challenging. Here, we report an improved method to generate ex vivo expanded NK (eNK) cells from MM patients based on genetic engineering of K562 cells to express OX40 ligand and membrane-bound (mb) IL-18 and IL-21. METHODS: K562-OX40L-mbIL-18/-21 cells were generated by transducing K562-OX40L cells with a lentiviral vector encoding mbIL-18 and mbIL-21, and these were used as feeder cells to expand NK cells from peripheral blood mononuclear cells of healthy donors (HDs) and MM patients in the presence of IL-2/IL-15. Purity, expansion rate, receptor expression, and functions of eNK cells were determined over four weeks of culture. RESULTS: NK cell expansion was enhanced by short exposure of soluble IL-18 and IL-21 with K562-OX40L cells. Co-culture of NK cells with K562-OX40L-mbIL-18/-21 cells resulted in remarkable expansion of NK cells from HDs (9,860-fold) and MM patients (4,929-fold) over the 28-day culture period. Moreover, eNK cells showed increased expression of major activation markers and enhanced cytotoxicity towards target K562, U266, and RPMI8226 cells. CONCLUSIONS: Our data suggest that genetically engineered K562 cells expressing OX40L, mbIL-18, and mbIL-21 improve the expansion of NK cells, increase activation signals, and enhance their cytolytic activity towards MM cells.

Prevalence and Risk Factors for Adrenal Insufficiency in Patients with Multiple Myeloma Receiving Long-Term Chemotherapy including Corticosteroids: A Retrospective Cohort Study.

Multiple myeloma (MM) is the second most common hematologic malignancy and requires long-term and high-dose corticosteroid-based chemotherapy. The aim of this study was to investigate the prevalence and clinical predictors of corticosteroid-associated adrenal insufficiency (AI) in patients with MM receiving long-term chemotherapy. This retrospective study included patients with MM who were administered corticosteroid-based chemotherapy and underwent a rapid adrenocorticotropic hormone (ACTH) stimulation test between 2005 and 2018. AI was determined by a peak cortisol value < 18 µg/dL after ACTH stimulation. Demographic, clinical, and laboratory parameters were evaluated, and the prevalence and clinical risk factors of AI were examined. Of 282 patients with MM who received corticosteroid-based chemotherapy, 142 patients (50.4%) were classified as having AI. There were no differences in age, sex, body mass index, comorbidities, and laboratory findings, including serum sodium levels between the AI and no-AI groups. In univariate analysis, the cumulative dose of corticosteroid (odds ratio (OR) = 0.99, 95% confidence interval (CI) 0.98-0.99; P = 0.020) and megestrol acetate use (OR = 2.63, 95% CI 1.48-4.67; P = 0.001) were associated with the occurrence of AI. Cumulative duration and cumulative dose per duration of corticosteroid use were not associated with the occurrence of AI. However, in the multivariate analysis, only megestrol acetate use was associated with an increased risk of AI (OR = 2.54, 95% CI 1.41-4.60; P = 0.002). Approximately 95.8% of patients with AI had suspicious symptoms or signs of AI. Although clinical symptoms and signs are usually nonspecific, symptomatic patients with MM receiving long-term corticosteroid therapy have sufficient potential for developing AI, particularly when receiving megestrol acetate. These findings can help alert clinicians to consider adrenal suppression following corticosteroid-based chemotherapy in patients with MM.

Expanded natural killer cells augment the antimyeloma effect of daratumumab, bortezomib, and dexamethasone in a mouse model.

The use of natural killer (NK) cells is a promising and safe immunotherapeutic approach in the field of cancer immunotherapy. However, combination treatments are required to enhance the effector functions and therapeutic efficacy of NK cells. In this study, we investigated the potential of daratumumab (Dara), bortezomib, and dexamethasone (Dvd) to augment the antitumor effects of NK cells in a multiple myeloma (MM) xenograft mouse model. NK cells were expanded and activated using the K562-OX40 ligand and membrane-bound IL-18 and IL-21 in the presence of IL-2 and IL-15 from peripheral blood mononuclear cells from MM patients. A human MM xenograft model was established using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγnull (NSG) mice. Tumor-bearing mice were divided into six treatment groups: no treatment, expanded NK cells (eNKs), Dara, Dara + eNKs, Dvd, and Dvd + eNKs. Dvd treatment strongly enhanced the cytotoxicity of eNKs by upregulating expression of NK cell activation ligands, downregulating expression of NK cell inhibitory ligands, and promoting antibody-dependent cellular cytotoxicity. The combination of eNKs with Dvd significantly prolonged mouse survival and reduced the tumor burden and serum M-protein level. Furthermore, Dvd pretreatment significantly increased eNK persistence and homing to MM sites. Our findings suggest that Dvd treatment potentiates the antimyeloma effects of NK cells expanded and activated ex vivo by modulating immune responses in MM-bearing mice.