Background
CD30, a 120 kDa surface phosphorylated protein is a member of tumour necrosis/nerve growth factor receptor (TNF/NGFR) family and constitutively expressed by Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL) and the neoplastic cells of Anaplastic Large Cell Lymphoma (ALCL). A disease-specific protein marker is yet to be identified in Hodgkin lymphoma cells. In order to define HL-specific biomarkers, novel murine monoclonal antibodies were developed in our laboratory.

/pdf/constitutive-overexpression-of-a-novel-21-kda-protein-by-5b70nc4eus.pdf

Constitutive overexpression of a novel 21 kDa protein by Hodgkin lymphoma and aggressive non-Hodgkin lymphomas.

Multiple myeloma (MM) is a complex disease with highly heterogeneous tumor biology, especially involving cytogenetic abnormalities.1 Consequently, MM patients display markedly diverse clinical characteristics, therapeutic responses, and outcomes.2,3 In this context, the international staging system (ISS) was developed to predict the prognosis of MM patients in 2005,4 which was later updated and named revised ISS (R-ISS) in 2015.5 Although the R-ISS has widely been used as a powerful tool to guide daily practice till present, some considerable limitations (eg, a large proportion of R-ISS II patients with varied outcomes, not reflecting the significance of 1q gain/amplification and concurrent high-risk cytogenetic abnormalities [HRCAs]) have been emerging.6–9 In this context, several new prognostic scoring systems have been reported,10,11 the most recent of which is the second revision of ISS (R2-ISS) updated by the European Myeloma Network (EMN).12 In the R2-ISS,12 5 risk variates with the highest impact on both progression-free survival (PFS) and overall survival (OS) were weighted according to their OS impact, including ISS III 1.5, ISS II 1.0, del(17p) 1.0, lactate dehydrogenase high 1.0, t(4;14) 1.0, and 1q+ (either 1q gain or amplification) 0.5. However, t(14;16) was not included because patients with this HRCA had only a trend toward a shorter PFS than those without it, but not statistically significant, although its role was significant in predicting OS. According to the R2-ISS, patients could be categorized into 4 groups with different risk scores that is, 0 (I), 0.5 to 1.0 (II), 1.5 to 2.5 (III), and 3.0 to 5.0 (IV). In 2 independent cohorts, the R2-ISS was able to sharply stratify newly diagnosed MM (NDMM) patients into these 4 groups with significantly different OS and PFS, including R2-ISS I (19.2% or 11.1% of all patients), II (30.8% or 26.5%), III (41.2% or 51.6%), and IV (8.8% or 10.7%). Moreover, the R2-ISS was able to predict the OS of both transplant-eligible and transplant-ineligible patients, and patients who received different upfront treatments (eg, proteasome inhibitors [PIs], immunomodulatory drugs [IMiDs], or both). Of note, this scoring system could further discriminate OS and PFS of R-ISS II patients, underlining its value in restratifying this large heterogeneous group of NDMM patients. With these advantages, this new simple algorithm would be expected to be applied soon in clinical practice to improve the performance of the currently using risk stratification systems such as R-ISS (especially further stratification of R-ISS II patients). However, since the R2-ISS was developed and validated in the European population of NDMM patients enrolled in multiple clinical trials, its prognostic property remains to be verified in other populations and in a real-world setting. In this context, the R2-ISS has recently been validated using real-world data in Australian and New Zealand population.13 Considering the significance of 1q+ in the R2-ISS, the Chinese population of NDMM patients may be particularly susceptible to this scoring system due to their high frequency (~50% of NDMM patients) of 1q+ and its prognostic value as reported earlier by our group.14 To this end, we carried out a retrospective analysis of the real-world data collected from daily practice to further validate the R2-ISS in a cohort of 1005 MM patients newly diagnosed between November 27, 2009 and November 20, 2019, at 6 centers nationwide in China (Table 1). This study was approved by the Institutional Review Boards of the First Hospital of Jilin University (Approval No. 2016-087). All patients had given written informed consent to the use of clinical data according to the Declaration of Helsinki. The inclusion criteria of this study were patients who had complete baseline information for R2-ISS scoring, particularly involving cytogenetics in CD138+ cells by fluorescence in-situ hybridization (FISH) that must include the probes for del(17p) (cutoff, 20%), t(4;14) (cutoff, 7.3%), and 1q+ (cutoff, 5.5%) including gain (3 copies) and amplification (≥4 copies) as described previously,14 and who must receive novel agents (PIs, IMiDs, or both) for upfront treatment. It is noteworthy that the cutoffs for some HRCAs such as t(4;14) and 1q+ was lower than those usually recommended, which might, at least in part, contribute to a relatively higher percentage of high-risk patients (eg, 1q+) in this cohort, thus representing one limitation of this study. All patients were treated in the real-world setting, of whom 511 (50.8%), 177 (17.6%), and 317 (31.5%) received PI-, IMiD-, and PI plus IMiD-based induction, and 122 (12.1%) received autologous stem cell transplantation (ASCT). According to the International Myeloma Working Group consensus criteria,15 114 (12.4%), 207 (22.6%), 244 (26.6%), 235 (25.6%), 58 (6.3%), and 59 (6.4%) of 917 evaluable patients had a stringent complete response, complete response, very good partial response, partial response, minimal response, and stable disease, respectively. PFS was defined as the time from diagnosis until disease progression, relapse, or death due to any cause. Patients who did not progress or relapse were censored on the last date when they were seen alive and event free. OS was defined as the time from diagnosis until death due to any cause or last follow-up.Table 1: Characteristics of Patients With Newly Diagnosed Multiple Myeloma in Our Cohort (n = 1005)With a median follow-up of 35.5 months (95% confidence interval [CI], 32.8-38.2), median PFS and OS were 25.2 (95% CI, 23.1-27.3) and 53.0 (95% CI, 48.1-57.9) months, respectively. A total of 1005 patients with NDMM were categorized into R-ISS I (118, 11.7%), II (624, 62.1%), and III (263, 26.2%), with the largest proportion of patients in the R-ISS II group.12 As expected, the R-ISS could clearly stratify NDMM patients on both PFS (Suppl. Figure S1A) and OS (Suppl. Figure S1B), with P < 0.001 for each comparison between R-ISS I, II, and III. According to the R2-ISS,12 all patients (n = 1005) were then scored and divided into 4 groups: R2-ISS I (75, 7.5%), II (160, 15.9%), III (582, 57.9%), and IV (188, 18.7%). Compared with those reported by the EMN,12 there were relatively fewer patients with low (R2-ISS I) and low-intermediate risk (R2-ISS II) but more patients with intermediate-high (R2-ISS III) and high risk (R2-ISS IV) in this cohort. Moreover, every group of patients in this cohort had also relatively shorter PFS and OS, consistent with the fact that majority of patients had more advanced disease, primarily due to late diagnosis, but much fewer patients received ASCT (a main limitation of this study) mostly due to unaffordability, in our cohort than those reported by the EMN (Suppl. Table S1). Of note, the differences in PFS (Figure 1A) and OS (Figure 1B) were significant for almost all comparisons between the 2 groups (P < 0.001), except R-ISS I versus II (PFS, P = 0.056; OS, P = 0.075), probably due to a relatively small number of low-risk patients (eg, ISS or R-ISS I) in our cohort. Moreover, the R2-ISS largely remained its risk-stratifying property in the subgroups of patients with different treatments, particularly in distinguishing the patients with R2-ISS III or IV from those with R2-ISS I or II. In addition, the R2-ISS might work well in patients who did not receive ASCT, for either age >65 years (Figure 1C and Suppl. Figure S2A) or age ≤65 years (Suppl. Figure S2B, C), compared with those who received ASCT (Suppl. Figure S3A, B). Similarly, the R2-ISS also separated patients with different risk levels in the ones who received either PI- or IMiD-based induction (Figure 1D and Suppl. Figure S4A) better than those who received PI plus IMiD-based induction (Suppl. Figure S4B, C). However, due to the small number of patients in some subgroups, these results should be interpreted with caution. Nonetheless, these observations support that the R2-ISS could well discriminate NDMM patients with different risk levels and predict their outcomes (both PFS and OS) at diagnosis, although treatments might influence its performance.Figure 1.: Survival of newly diagnosed multiple myeloma (NDMM) patients according to the R2-ISS. (A, B) PFS (A; median: 48.7, 37.5, 24.3, and 16.3 mo for R2-ISS I–IV, respectively) and OS (B; median: 139.0, 82.2, 51.8, 29.5 mo for R2-ISS I–IV, respectively) of all patients (n = 1005). (C) OS of patients with age >65 y (n = 314; median: 125.3, not reached [NR], 43.3, and 30.5 mo for R2-ISS I–IV, respectively). (D) OS of patients who received either proteasome inhibitor (PI)- or immunomodulatory drug (IMiD)-based induction (n = 688; median: 139.0, 82.8, 49.7, and 27.1 mo for R2-ISS I-IV, respectively). (E, F) PFS (E; median: 39.6, 25.3, and 21.3 mo for R2-ISS II–IV, respectively) and OS (F; median: 82.2, 53.8, and 40.5 mo for R2-ISS II–IV, respectively) of R-ISS II patients (n = 624). OS = overall survival; PFS = progression-free survival; R2-ISS = second revision of international staging system.One of the main aims for developing the R2-ISS is to better stratify R-ISS II patients,12,13 which account for about 60% of patients with considerably heterogeneous outcomes in this cohort. We thus validated whether the R2-ISS would be able to restratify the R-ISS II patients and predict their outcomes more precisely. In R-ISS II patients (n = 624), there were 117 (18.8%), 486 (77.9%), and 21 (3.4%) patients with R2-ISS II, III, and IV (Suppl. Figure S4D). The differences in PFS (Figure 1E) and OS (Figure 1F) were statistically different between R2-ISS II versus III or IV (P < 0.01 for each comparison), consistent with those reported by the EMN.12 However, no significant difference was observed between R2-ISS III and IV (P > 0.05 for both PFS and OS), similar to the results from the training set, but not the validation set, in the study reported by the EMN.12 Moreover, a comparison of patient outcomes between R-ISS and R2-ISS suggests that the capability to further restratify R-ISS II patients might represent an advantage for the R2-ISS (Suppl. Table S2). Therefore, these observations support the notion that the R2-ISS could restratify patients with R-ISS II, particularly in the case of distinguishing R2-ISS III and IV from R2-ISS II. In summary, this study provides the evidence for the value of the R2-ISS recently updated by the EMN in the risk stratification of NDMM patients, particularly those categorized as R-ISS II by the R-ISS staging system, in an entirely independent cohort of patients with considerable differences in baseline characteristics (eg, more advanced disease and HRCAs) and treatments (ie, in the real-world setting, rather than clinical trials in the EMN study12). Thus, this new simple prognostic tool warrants further attention in future investigations and practice. AUTHOR CONTRIBUTIONS PY, FZ, YD(1), GG, HX, XL, SY, WX, YM, XQ, ML, YD(2), and FJ performed the research. FJ, PY, and YD(2) analyzed and interpreted the data. FJ and YD(2) conceived and planned the study design, and wrote the article. All authors approved the article. DATA AVAILABILITY Original data are available upon reasonable request to corresponding authors. DISCLOSURES The authors have no conflicts of interest to disclose. SOURCES OF FUNDING This work was supported by the National Natural Science Foundation of China (Grant Nos. 81471165, 81670190, 81670189, 81870160, 81971108, and 82270207) and Science and Technology Development Program of the Jilin Province (Grant Nos. 20190201042JC, 20190201163JC, and 20210509010RQ), and Interdisciplinary Integration and Innovation Project of Jilin University. 

The R2-ISS in a Multicenter Cohort of Chinese Patients With Newly Diagnosed Multiple Myeloma

Key Points • The R2-ISS system can stratify patients with MM receiving autologous stem cell transplantation.• Demographic and clinical variables (eg, age and platelet count) significantly affect survival prediction accuracy in the R2-ISS model.

Application of R2-ISS risk stratification to patients with multiple myeloma treated with autologous stem cell transplants at UAMS

ultiple myeloma (MM) is a complex disease with highly heterogeneous tumor biology, especially involving cytogenetic abnormalities. 1 Consequently, MM patients display markedly diverse clinical characteristics, therapeutic responses, and outcomes. 2,3 In this context, the international staging system (ISS) was developed to predict the prognosis of MM patients in 2005, 4 which was later updated and named revised ISS (R-ISS) in 2015. 5 Although the R-ISS has widely been used as a power-ful tool to guide daily practice till present, some considerable limitations (eg, a large proportion of R-ISS II patients with var-ied outcomes, not reflecting the significance of 1q gain/ampli- fication and concurrent high-risk cytogenetic abnormalities [HRCAs]) have been emerging. 6–9 In this context, several new prognostic scoring systems have been reported, 10,11 the most recent of which is the second revision of ISS (R2-ISS) updated by the European Myeloma Network (EMN). 12 In the R2-ISS, 12 5 risk variates with the highest impact on both progression-free survival (PFS) and overall survival (OS) were weighted according to their OS impact, including ISS III 1.5, ISS II 1.0, del(17p) 1.0, lactate dehydrogenase high 1.0, t(4;14) 1.0, and 1q+ (either 1q gain or amplification) 0.5. However, t(14;16) was not included because patients with this HRCA had only a

Summary Patients with multiple myeloma (MM) with chromosome 1q21 Gain (1q21+) are clinically and biologically heterogeneous. 1q21+ in the real world actually reflects the prognosis for gain/amplification of the CKS1B gene. In this study, we found that the copy number of prune exopolyphosphatase 1 ( PRUNE1 ), located on chromosome 1q21.3, could further stratify the prognosis of MM patients with 1q21+. Using selected reaction monitoring/multiple reaction monitoring (SRM/MRM) analysis, liquid chromatography–tandem mass spectrometry (LC–MS/MS), transmission electron microscopy (TEM), confocal fluorescence microscopy, calculation of adenosine triphosphate (ATP), intracellular reactive oxygen species (ROS) and mitochondrial oxygen consumption rates (OCRs), we demonstrated for the first time that PRUNE1 promotes the proliferation and invasion of MM cells by stimulating purine metabolism, purine synthesis enzymes and mitochondrial functions, enhancing links between purinosomes and mitochondria. SOX11 was identified as a transcription factor for PRUNE1. Through integrated analysis of the transcriptome and proteome, CD73 was determined to be the downstream target of PRUNE1. Furthermore, it has been determined that dipyridamole can effectively suppress the proliferation of MM cells with high‐expression levels of PRUNE1 in vitro and in vivo. These findings provide insights into disease‐causing mechanisms and new therapeutic targets for MM patients with 1q21+. 

<scp>PRUNE1</scp> (located on chromosome 1q21.3) promotes multiple myeloma with 1q21 Gain by enhancing the links between purine and mitochondrion

To the Editor: With the introduction of novel agents, more than 80% of patients with newly-diagnosed MM (NDMM) can achieve complete remission (CR) or better after first-line treatment. However, the majority of these patients eventually experience relapse, therefore calling for an additional approach to more precisely evaluate the depth of response and estimate the outcomes. Minimal residual disease (MRD) has been emerging as a reliable surrogate endpoint for progression-free survival (PFS) in clinical trials, while undetectable MRD strongly correlates with favorable outcomes, including both PFS and overall survival (OS). Over 50 ongoing phase III trials have included MRD as an endpoint to evaluate the depth of therapeutic response or assign MRD-directed treatment. Thus, MRD has been included into the revised International MyelomaWorking Group (IMWG) criteria for assessment of therapeutic response. Moreover, the prognostic value of MRD seems independent of baseline risk factors such as advanced disease stage (e.g., ISS or R-ISS III) and high-risk cytogenetic abnormality (HRCA). However, several key issues remain to be addressed for incorporating the MRD test into daily practice. To this end, we conducted this retrospective study to explore the significance of dynamic monitoring of the MRD status in the management of NDMM patients. This study was approved by the Institutional Review Board (IRB) of the First Hospital of Jilin University (approval # 2018-087). The study included patients with NDMM who had flow cytometry-based MRD test at least twice after initiation of treatment, between March 2015 and June 2019. CAs were assessed by FISH in CD138 cells isolated from bone marrow (BM) samples via routine diagnostic procedures. Among them, del(17p), t(4;14), t(14;16), and + 1q (1q21 gain/ amplification) were considered as HRCAs. Therapeutic responses were evaluated according to the IMWG consensus criteria. The first MRD test was conducted at the time when an objective response (e.g., PR, VGPR, CR, or sCR) was achieved during induction or consolidation. MRD was evaluated in bone marrow (BM) samples (1.5 10 cells per sample) using a modified 2-tube 8-color assay (tube 1: cKappa-FITC/cLambda-PE/CD138-Percp-cy5.5/CD27-PE-CY7/CD22APC/CD19-APC-H7/CD38-BV421/CD45-Viogreen; tube 2: CD56FITC/CD200-PE/CD28-Percp-cy5.5/CD117-PE-CY7/CD19-APC/ CD20-APC-H7/CD38-BV421/CD45-Viogreen.) by Navios flow cytometer (Beckman Coulter) in a single clinical laboratory. Two million cellular events were analyzed using the Kaluza Analysis Software to determine the percentage of phenotypically aberrant clonal plasma cells (PCs) in total nucleated cells. The limit of detection (LOD) achieved was calculated in each sample according to the following formula: (20/number of viable nucleated cells) 100. Undetectable MRD was defined as the absence of phenotypically aberrant clonal PCs or their percentage below the LOD (median 3.46 10 ), while detectable MRD was defined as the percentage of phenotypically aberrant clonal PCs equal to or greater than the LOD. Duration of undetectable MRD was defined as the time from the first detection of undetectable MRD to reappearance of detectable MRD. PFS was defined as the time from the first day of treatment until the date when disease progression, relapse, or death was first reported. OS was defined as the time from the first day of treatment until the date of death due to any cause or last follow-up. All statistical analyses were conducted using SPSS software (version 22.0) and R packages survival and survminer in R/Bioconductor (version 3.6.1). p < .05 was considered significant. A total of 220 patients with NDMM were assessed for MRD at least twice, with median of three times (range 2–11). The first test was conducted at initial objective responses, including PR (38.2%), very good partial response (VGPR, 19.1%), and ≥ CR (42.7%). Among them, 114 patients attained undetectable MRD (MRD ), while 106 patients had persistent MRD (MRD). To examine whether baseline variables would influence the MRD status, clinical characteristics and treatment were compared between MRD and MRD (Table S1). Interestingly, patients with ≥2 HRCAs (named double-hit) had lower rate of MRD attainment (25.0%) than those with one HRCA (53.9%; p = .007). With the median follow-up time of 33.3 months, the Kaplan– Meier curve revealed that attainment of MRD substantially prolonged PFS (Hazard ratio/HR, 0.19, 95% CI, 0.12–0.28, p < .0001; Figure S1A) and OS (HR, 0.25, 95% CI, 0.15–0.42, p < .0001; Figure S1B). Similar results were obtained in the subgroup of elderly patients (age ≥ 65 years), including PFS (p < .0001; Figure S1C) and OS (p = .0049; Figure S1D). Whereas the time-to-MRD varied, virtually all MRD patients achieved MRD within a year (70% within half a year) after initiation of treatment (not shown). Accordingly, 1-year landmark analysis was conducted and revealed that MRD were significantly associated with prolonged PFS (p < .001 for both time periods; not shown) and OS (Figure 1A) within or beyond 1 year. Three-year PFS rate of MRD and MRD patients was 58.9% versus 12.4%; 5-year OS rate of MRD and MRD patients was 67.5% versus 21.7%. Subgroup analysis according to the MRD status revealed that the favorable impact of MRD on both PFS (Figure S1E) and OS (Figure S1F) was consistent across all subgroups categorized by various risk factors at diagnosis. Following the univariate analysis Received: 14 November 2022 Revised: 5 December 2022 Accepted: 6 December 2022

Dynamic monitoring of minimal residual disease in newly‐diagnosed multiple myeloma

OBJECTIVE To study the clinicopathologic and immunohistochemical features of diffuse large B-cell lymphoma (DLBCL) and the significance of immunohistochemistry in diagnosis and differential diagnosis of DLBCL. METHODS 60 cases of DLBCL were studied and immunohistochemical staining for LCA, L26, BLA-36, CD30, bcl-6 were carried out with the EnVision 2 step method. RESULTS The age range of 76.7% (46/60) patients was 40 - 70 years. The location of the lesion includes nodal and extranodal sites. 90.0% (54/60) were in clinical stages of II (24/54), III (21/54), IV (9/54). Histopathologic morphology presented as centroblastic (88.3%, 53/60), immunoblastic (3.3%, 2/60), anaplastic large B cell type (3.3%, 2/60) and T cell rich B cell type (5.0%, 3/60). Immunostaining showed 100% (60/60) DLBCL were positive for LCA, L26, BLA36, 3.3% (2/60) DLBCL positive for CD30, 95% (57/60) expressed bcl-6 protein. CONCLUSIONS DLBCL is an aggressive lymphoma which shows cytologic variability from case to case. The evaluation of pathologic features and immunohistochemistry in DLBCL are useful and practical for diagnostic purposes, but cannot delineate distinctive morphologic subtypes.

A clinicopathologic and immunohistochemical study of diffuse large B-cell lymphoma.

/pdf/early-leukoencephalopathy-during-daratumumab-treatment-in-a-uad3c39u.pdf

Early leukoencephalopathy during daratumumab treatment in a patient with multiple myeloma

More than 2% circulating plasma cells as a prognostic biomarker in a large cohort of patients with newly-diagnosed multiple myeloma.

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