Solitary bone plasmacytoma: Long-term clinical outcomes in a single center.

BACKGROUND: A solitary plasmacytoma is classified into a solitary plasmacytoma of the bone (SBP) and a solitary extramedullary (soft tissue mass) plasmacytoma, based on the site of the lesion. Despite the high local control rate with radiotherapy, approximately half of patients' conditions progress to multiple myeloma (MM) within 3-5 years after diagnosis, with SBP having a worse prognosis. PATIENTS AND METHODS: We retrospectively assessed the treatment and outcomes of patients with SBP in a hospital in China from 2008 to 2021. Twenty-four patients treated over 13 years with SBP were enrolled in this retrospective study. RESULTS: The most common sites for SBP were the axial skeleton and femur. The M protein was detected in 11 patients (46 %), of which 8 (33 %) had light chains, 2 (8 %) had immunoglobulin G kappa and 1 (4 %) had immunoglobulin D kappa. Flow cytometry revealed that 5 patients (21 %) had minimal bone marrow involvement. The treatment included chemotherapy, surgery, and radiotherapy in 18 (75 %), 12 (50 %), and 9 (38 %) patients, respectively, of whom 13 (54 %) received combined treatment. Over a median follow-up period of 67.2 months, 9 patients (38 %) developed MM in a median time of 101.5 months. The 5- and 10-year progression-free survival rates were 67.3 % and 37.4 %, respectively. One patient died due to pneumonia without progression and the other died due to relapse. CONCLUSION: This study confirmed the high rate of progression of SBP to MM, indicating a need for adjunct chemotherapy for the management of SBP.

Validation of the IMPEDE VTE score for prediction of venous thromboembolism in Chinese patients with multiple myeloma: A single-center retrospective cohort study.

Multiple myeloma (MM) significantly increases the risk of venous thromboembolism (VTE) within 6 months of treatment initiation. The IMPEDE VTE score is a VTE risk prediction model which is recently incorporated into the National Comprehensive Cancer Network (NCCN) guidelines, but it lacks validation among Asians, including Chinese MM patients. We performed a retrospective chart review of 405 Chinese with newly diagnosed MM who started therapy at Beijing Jishuitan Hospital between April 2013 to October 2022. The 6-month cumulative incidence of VTE was 3.8 % (95 % CI:1.6-7.6), 8.6 % (95 % CI: 5.3-21.9) and 40.5 % (95 % CI: 24.9-55.7) in the low-, intermediate- and high-risk groups (P < 0.001), respectively. The C-statistic of the IMPEDE VTE scores for predicting VTE within 6 months of treatment initiation was 0.74 (95 % CI: 0.65-0.83). Of note, in this single-center cohort study, we propose that the anticoagulant LMWH may be more effective than the antiplatelet aspirin in potentially preventing VTE in newly diagnosed MM patients. Our findings suggest that the IMPEDE VTE score is a valid evidence-based risk stratification tool in Chinese patients with newly diagnosed MM.

Ixazomib-based frontline therapy followed by ixazomib maintenance in frail elderly newly diagnosed with multiple myeloma: a prospective multicenter study.

Background: Frail elderly patients with newly diagnosed multiple myeloma (NDMM) have inferior survival and less benefit from high-dose therapies. This prospective study aimed to investigate the efficacy, safety, and quality of life (QoL) of induction treatment of ixazomib/lenalidomide/dexamethasone (IRd) and ixazomib/pegylated liposomal doxorubicin/dexamethasone (IDd) followed by ixazomib/dexamethasone (Id) maintenance therapy in frail, elderly patients with NDMM. Methods: From July 2019 to December 2021, this non-randomized concurrent controlled clinical study enrolled 120 NDMM patients aged ≥65 years with frailty defined by the International Myeloma Working Group (IMWG) frailty score or Mayo geriatric scoring system. The enrolled patients received 6-8 cycles of IRd or IDd followed by Id maintenance therapy for a minimum of 2 years at the discretion of physicians based on patient's clinical characteristics (chiCTR1900024917). Findings: The median age was 71 years and 55% of the patients were males. The overall response rate (ORR) was 82% and 77%, complete response (CR) rate was 25% and 12% for IRd and IDd groups, respectively. The difference in ORR of the Idd group minus the IRd group was -5.36% (95% CI: -18.9% to 8.19%), indicating that the ORR of the IDd group was neither inferior nor non-inferior to the IRd group. After a median follow-up of 34.3 months, the median progression-free survival (PFS) was 21.6 and 13.9 months, OS was not reached and 29.2 months in IRd and IDd groups, respectively. 28 and 33 patients discontinued induction therapy, 20 and 19 discontinued maintenance therapy in IRd and IDd groups, respectively. Cumulative Grade 3 or higher hematological adverse events (AEs) occurred in 10 of the 60 patients (17%) and non-hematological AEs occurred in 15 of the 60 patients (25%) in the IRd group, while 13 of the 60 patients (22%) and 21 of the 60 patients (35%) in the IDd group. Patients were observed with clinically significant improvement in QoL when compared with that at baseline in both IRd and IDd groups by evaluation per cycle (P < 0.0001). Interpretation: The results demonstrated that compared with IRd regimen, IDd regimen showed no significant advantage, but the survival of the IDd group was shorter than that of the IRd group, indicating an all-oral outpatient triplet regimen with IRd, which has low toxicity and has improved QoL, could be the viable first-line treatment option for frail NDMM patients. Funding: The Young Elite Scientist sponsorship program by bast of Beijing Association for Science and Technology (No. BYESS2023116) and Beijing Medical Award Foundation (No. YXJL-2018-0539-0073).

Identification of aberrantly expressed lncRNAs and ceRNA networks in multiple myeloma: a combined high-throughput sequencing and microarray analysis.

Background: This study aimed to explore the potential effects of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) patients using two detection methods: high-throughput sequencing and microarray. Methods: In this study, lncRNAs were detected in 20 newly diagnosed MM patients, with 10 patients analyzed by whole transcriptome-specific RNA sequencing and 10 patients analyzed by microarray (Affymetrix Human Clariom D). The expression levels of lncRNAs, microRNAs, and messenger RNAs (mRNAs) were analyzed, and the differentially expressed lncRNAs identified by both methods were selected. The significant differentially expressed lncRNAs were further validated using PCR. Results: This study established the aberrant expression of certain lncRNAs involved in the occurrence of MM, with AC007278.2 and FAM157C showing the most significant differences. The top 5 common pathways identified by the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were the chemokine signaling pathway, inflammatory mediator regulation, Th17 cell differentiation, apoptosis, and NF-kappa B signaling pathway. Furthermore, three microRNAs (miRNAs) (miR-4772-3p, miR-617, and miR-618) were found to constitute competing endogenous RNA (ceRNA) networks in both sequencing and microarray analyses. Conclusions: By the combination analysis, our understanding of lncRNAs in MM will be increased significantly. More overlapping differentially expressed lncRNAs were found to predict therapeutic targets precisely.

Vitamin D deficiency linked to abnormal bone and lipid metabolism predicts high-risk multiple myeloma with poorer prognosis.

Purpose: Vitamin D deficiency is frequent in patients with multiple myeloma (MM), however, its prognostic relevance in MM was rather inconclusive. We first investigated the association of vitamin D deficiency with abnormal bone and lipid metabolism in newly diagnosed multiple myeloma (NDMM), and next assessed the impact of serum ratio of vitamin D to carboxy-terminal telopeptide of type I collagen (ß-CTX) on progression-free survival (PFS) and overall free survival (OS) in patients with NDMM. Methods: The data of 431 consecutive patients with NDMM at Beijing Jishuitan Hospital from September 2013 to December 2022 were collected and retrospectively reviewed through our electronic medical record system. The measurement of 25-hydroxyvitamin D in the blood is an indicator of an individual's overall vitamin D status. Results: The serum levels of vitamin D were negatively correlated with ß-CTX in NDMM patients. Of note, positive correlation between vitamin D and cholesterol levels in the serum was found in this study. The cohort (n = 431) was divided into two groups based on the serum ratio of vitamin D to ß-CTX. Compared to the group with a higher vitamin D to ß-CTX ratio, the group with a lower vitamin D to ß-CTX ratio (n = 257, 60%) exhibited hypocholesterolemia, inferior PFS and OS, along with increased cases of ISS stage-III and R-ISS stage-III, a higher number of plasma cells in the bone marrow, and elevated serum calcium levels. Consistent with this, multivariate analysis confirmed that the vitamin D to ß-CTX ratio was an independent unfavorable indicator for survival in NDMM patients. Conclusion: Our data demonstrated the ratio of vitamin D to ß-CTX in the serum is a unique biomarker for NDMM patients to identify the high-risk cases with poor prognosis, which is superior to vitamin D itself for predicting PFS and OS in NDMM. Also, it is worth mentioning that our data on the connection between vitamin D deficiency and hypocholesterolemia might help clarify novel mechanistic aspects of myeloma development.

Risk-benefit ratio of percutaneous kyphoplasty and percutaneous vertebroplasty in patients with newly diagnosed multiple myeloma with vertebral fracture: a single-center retrospective study.

The indications for percutaneous kyphoplasty (PKP) and percutaneous vertebroplasty (PVP) are painful vertebral compression fractures. Our study is to assess the risk-benefit ratio of PKP/PVP surgery in the patients with newly diagnosed multiple myeloma (NDMM) without receiving antimyeloma therapy. The clinical data of 426 consecutive patients with NDMM admitted to our center from February 2012 to April 2022 were retrospectively analyzed. The baseline data, postoperative pain relief, the proportion of recurrent vertebral fractures, and survival time were compared between the PKP/PVP surgical group and the nonsurgical group in the NDMM patients. Of the 426 patients with NDMM, 206 patients had vertebral fractures (206/426, 48.4%). Of these, 32 (32/206, 15.5%) underwent PKP/PVP surgery for misdiagnosis of simple osteoporosis prior to diagnosis of MM (surgical group), and the other 174 (174/206, 84.5%) did not undergo surgical treatment prior to definitive diagnosis of MM (non-surgical group). The median age of patients in the surgical and nonsurgical groups was 66 and 62 years, respectively (p = 0.01). The proportion of patients with advanced ISS and RISS stages was higher in the surgical group (ISS stage II + III 96.9% vs. 71.8%, p = 0.03; RISS stage III 96.9% vs. 71%, p = 0.01). Postoperatively, 10 patients (31.3%) never experienced pain relief and 20 patients (62.5%) experienced short-term pain relief with a median duration of relief of 2.6 months (0.2-24.1 months). Postoperative fractures of vertebrae other than the surgical site occurred in 24 patients (75%) in the surgical group, with a median time of 4.4 months postoperatively (0.4-86.8 months). Vertebral fractures other than the fracture site at the first visit occurred in 5 patients (2.9%) in the nonoperative group at the time of diagnosis of MM, with a median time of 11.9 months after the first visit (3.5-12.6 months). The incidence of secondary fractures was significantly higher in the surgical group than in the nonsurgical group (75% vs. 2.9%, p = 0.001). The time interval between the first visit and definitive diagnosis of MM was longer in the surgical group than in the nonsurgical group (6.1 months vs. 1.6 months, p = 0.01). At a median follow-up of 32 months (0.3-123 months), median overall survival (OS) was significantly shorter in the surgical group than in the nonsurgical group (48.2 months vs. 66 months, p = 0.04). Application of PKP/PVP surgery for pain relief in NDMM patients without antimyeloma therapy has a limited effect and a high risk of new vertebral fractures after surgery. Therefore, patients with NDMM may need to have their disease controlled with antimyeloma therapy prior to any consideration for PKP/PVP surgery.

Clinical and genomic characterization of Chinese patients with functional high-risk multiple myeloma: A real-world validation study.

Objective: Precise risk stratification is increasingly essential in the management of multiple myeloma (MM) as some standard-risk (SR) patients still exhibit similar poor outcomes as genetically high-risk (GHR) patients in the era of novel agents. It has recently been demonstrated that functional high-risk (FHR) patients, those with suboptimal response to first-line induction therapy or early relapse within 12 months, have identifiable molecular characteristics from the SR group in the CoMMpass dataset. However, these findings lack practical validation in the real world. Methods: MM cells purified by CD138 microbeads from newly diagnosed MM (NDMM) patients received fluorescence in situ hybridization and sequencing with a 92-gene Panel. Cytogenetic abnormalities defined GHR patients with t(4;14) or t(14;16) or complete loss of functional P53 or 1q21 gain and International Staging System (ISS) stage 3. SR group was patients who did not fulfill any criteria for GHR or FHR. Results: There were 145 patients with NDMM, 78 in the SR group, 56 in the GHR group, and 11 in the FHR group. In the FHR group, eight patients were suboptimal responses to induction therapy, and three relapsed within 12 months. We found that male patients, patients with extra-medullary plasmacytoma (EMD), circulating clonal plasma cells (CPC) ≥0.05%, and P53 mono-allelic inactivation were significantly higher in the FHR group compared to the SR group. After a median follow-up of 21.0 months, the median progression-free survival (PFS) and overall survival (OS) were 5.0 months, 19.1 months and 36.6 months in the FHR, GHR, and SR groups, respectively. Compared to the SR group, FHR patients had a higher frequency of mutations in MKI67, ERN1, and EML4. GO analysis showed that mutations in FHR were enriched for oxidative stress, chromosomal segregation, and hypoxia tolerance. Conclusion: The FHR found in the SR NDMM patient group has unique clinical features, including being male, with EMD and CPC, and genetic characteristics of mutations affecting oxidative stress, chromosome segregation, and hypoxia tolerance. In contrast to previous reports, our data suggested that patients with P53 mono-allelic inactivation should be classified in the GHR group rather than the FHR group.

Front-line treatment efficacy and clinical outcomes of elderly patients with multiple myeloma in a real-world setting: A multicenter retrospective study in China.

BACKGROUND: The use of proteasome inhibitors (PIs), new immune modulators (IMiDs), and other new drugs, as well as high-dose chemotherapy combined with autologous stem cell transplantation has considerably improved the survival of young patients with multiple myeloma (MM). However, the improvement in survival among elderly patients remains insufficient. Optimal treatment recommendation models for elderly patients with MM have not been developed especially there are quite few study in the real world. METHODS: We retrospectively analyzed the treatment patterns and outcomes of 328 Chinese patients (≥65 years) with MM in a real-world setting. Patients were divided into three groups according to induction regimens. RESULTS: The median age of the cohort was 70 (65-86) years. The patients were divided into group 1 (PIs based regimens, n = 218), group 2 (IMiDs based regimens, n = 48) and group 3 (PIs + IMiDs, n = 62). Induction regimens in group 3 produced higher overall response rate than group 1 and 2 (85.42% vs. 71.08% vs. 66.67%, p = 0.016). The median follow-up of the cohort was 30 (interquartile range [IQR] 18-36) months. For the entire cohort median progression-free survival (PFS) was 26 (IQR 12.00-42.89) months and overall survival (OS) was 60 (IQR 40.00-67.20) months. The PFS were not significantly different among the three groups (28 months vs. 18 months vs. 26 months, p = 0.182). So were the OS (60 months vs. 59 months vs. not reached, p = 0.067). Multivariate analysis revealed that age >70 year, frailty status (Geriatric vulnerability score), induction efficacy < partial remission, and no maintenance treatment were independent poor prognostic factors for OS. CONCLUSION: Front-line induction regimens combining PIs and IMiDs developed more deep response than single PI or IMiD based regimens. Maintenance treatment can further improve the clinical outcome in elderly MM patients in real-world setting.

Machine Learning-Based Overall Survival Prediction of Elderly Patients With Multiple Myeloma From Multicentre Real-Life Data.

Objective: To use machine learning methods to explore overall survival (OS)-related prognostic factors in elderly multiple myeloma (MM) patients. Methods: Data were cleaned and imputed using simple imputation methods. Two data resampling methods were implemented to facilitate model building and cross validation. Four algorithms including the cox proportional hazards model (CPH); DeepSurv; DeepHit; and the random survival forest (RSF) were applied to incorporate 30 parameters, such as baseline data, genetic abnormalities and treatment options, to construct a prognostic model for OS prediction in 338 elderly MM patients (>65 years old) from four hospitals in Beijing. The C-index and the integrated Brier score (IBwere used to evaluate model performances. Results: The 30 variables incorporated in the models comprised MM baseline data, induction treatment data and maintenance therapy data. The variable importance test showed that the OS predictions were largely affected by the maintenance schema variable. Visualizing the survival curves by maintenance schema, we realized that the immunomodulator group had the best survival rate. C-indexes of 0.769, 0.780, 0.785, 0.798 and IBS score of 0.142, 0.112, 0.108, 0.099 were obtained from the CPH model, DeepSurv, DeepHit, and the RSF model respectively. The RSF model yield best scores from the fivefold cross-validation, and the results showed that different data resampling methods did affect our model results. Conclusion: We established an OS model for elderly MM patients without genomic data based on 30 characteristics and treatment data by machine learning.

Amp 1q21 is more predictable with dismal survival than gain 1q21 of newly diagnosed multiple myeloma in real-world analysis.

INTRODUCTION: The gain/amplification (amp) of 1q21 is one of the most common high-risk chromosome abnormality (HRCA) in multiple myeloma (MM). The prognostic value of 1q21+ remains to be controversial on the status of gain or amp and the combination of other HRCAs. METHODS: In this retrospective study, we included 318 newly diagnosed MM (NDMM) patients who had fluorescence in situ hybridization (FISH) data and treated with novel agents in our department. RESULTS: Our study noted MM patients with amp 1q21 were more likely accompanied with t(4;14), t(14;16), and t(14;20). Patients with amp 1q21 presented with elder age, advanced Revised International Staging System (R-ISS) stages, anemia, and more plasma cells in bone marrow compared to patients with gain 1q21 alone and no 1q21+. Moreover, amp 1q21 alone correlated with shorter progression-free survival (PFS) (22.8m vs. 40.5m vs. 39.6m) and overall survival (OS) (45.2m vs. NA vs. 83.5m) compared with gain 1q21 alone and no FISH abnormalities. Although the high ratio of proteasome inhibitor and immunomodulatory drugs used in patients with amp 1q21, the overall response (ORR) was the lowest compared with no 1q21+ and gain 1q21. Multivariate analysis defined amp 1q21 as an independent prognostic marker for NDMM patients, rather than gain 1q21. CONCLUSION: The amp 1q21 predict inferior treatment response and survival, especially coexisted with high-risk IgH translocation.

[The Significance of CD319 and CD269 in the Detection of Immunophenotyping and Minimal Residual Disease in Multiple Myeloma Patients].

OBJECTIVE: To investigate the expression of CD319 and CD269 in plasma cells of patients with multiple myeloma (MM) and the feasibility of using CD319 instead of CD38 as a gating antigen in immunophenotyping and minimal residual disease (MRD) monitoring. METHODS: The expression levels of CD319 and CD269 antigens in clonal bone marrow plasma cells of 387 patients were detected by CD38/CD138 gating strategy with 8-color flow cytometry, and the stability of antigens was also analyzed, and the sensitivity and correlation of two different gating strategies employing CD319/CD138 and CD38/CD138 were compared as well. The control group consisted of 53 cases with non-malignant blood disease matched by age and sex. RESULTS: Monoclonal plasma cells were detected in 303 of 387 MM patients, among which 277 cases (91.42%) were positive for CD269, and all cases were positive for CD319 (100%). In newly diagnosed MM (NDMM) and recurrent refractory MM (RRMM) patients, the expression levels of CD269 were 97.53% (0-99.92%) and 94.96% (0.22%-99.99%), respectively, while levels of CD319 were 99.90% (87.77%-100%) and 99.78% (63.12%-100%), respectively. The expression levels of CD269 and CD319 in the control group were 97.00% (77.00%-100%) and 100% (89.00%-100%), respectively. There were no significant differences in the expression levels of CD269 and CD319 among NDMM, RRMM and the control group. Patients acquiring therapeutic effects were divided into complete remission (CR) group, very good partial response (VGPR) group and partial response (PR) group. Gating with CD38/CD138, median MRD values were 0.76% (0-1.88%), 0.77% (0-4.96%) and 1.75% (0.09%-10.90%) in the three groups, respectively, while gating with CD319/CD138, median MRD values were 0.57% (0.18%-1.96%), 1.07% (0.12%-4.85%) and 1.77% (0.08%-8.22%), respectively. There was no significant difference in MRD level by the two gating strategies, but a good correlation between the two (r=0.808, P<0.05). In addition, in 4 patients treated by CD38 monoclonal antibody (DARA), the expression level of CD38 was observed to be down-regulated or even negative after treatment. When the MRD level was very low, CD38/CD138 gating resulted in false MRD-, while CD319/CD138 gating resulted in MRD+. CONCLUSION: CD319 and CD269 express stably and continuously in plasma cells of MM patients at different disease stages. CD319 can be used as an alternative of CD38 for immunophenotyping and MRD detection, especially for MRD detection after DARA treatment, while CD269 is suitable for detection before BCMA-CAR-T treatment.

[Induction of apoptosis of leukemic tumor cells in mouse model with G-quadruplex ligand Tel03].

This study was aimed to investigate the anti-leukemia activity of Tel03 in vivo. The K562 xenografted leukemia model was established and mice were divided randomly into three groups. Mice of different group were treated with PBS (control), 5 mg/kg Tel03 or 15 mg/kg Tel03 (ip, twice a week) respectively. Tumor volume, body weight and other behavior were observed regularly. Cell apoptosis was detected with TUNEL assay and the expression levels of Bcl-2 and Bax were detected by Western blot. The results indicated that Tel03 exerted anti-leukemia activity in mouse model. Tel03 significantly reduced tumor volume in Tel03-treated group compared with control. In addition, 5 mg/kg Tel03 induced cell apoptosis without exerting apparent toxicity in mice. After Tel03 treatment, the expression of Bcl-2 was inhibited, however, the expression of Bax was up-regulated. It is concluded that G-quadruplex ligand Tel03 can induce cell apoptosis in leukemia mouse model, and this agent may be a potential anticancer drug.

[A study of cellular telomerase activity in different stages of multiple myeloma cells].

OBJECTIVE: To evaluate the clinical significance of telomerase in multiple myeloma (MM) and explore its relationship with cell cycle. METHODS: Marrow plasma cells were collected form 21 patients with newly diagnosed or relapsed MM, 2 patients with monoclonal gammopathy of undetermined significance (MGUS), 15 MM patients in complete remission and 10 donors as control. PC isolation from the marrow mononuclear cell fraction was performed using immunomagnetic bead selection with CD(138) antibodies. Telomerase activity was detected with TRAP (Telomerase repeats amplification protocol)-fluorescence. Cell cycle was assayed by flow cytometry. RESULTS: (1) The results showed that the positive rate of telomerase in all the newly diagnosed and relapsed patients was 90.5%, which was higher than that in the control group (10.0%) and the patients in remission (13.3%) (P < 0.01). There was no significant difference between the patients in remission and control group (P > 0.05), as well as between newly diagnosed and relapsed patients (P > 0.05). (2) The average percentage of S period in the telomerase positive patients was (18.78 +/- 8.02)%, while that in the negative patients was (5.64 +/- 4.03)%; there was statistics difference between them (P < 0.05). CONCLUSIONS: (1) Telomerase plays an important role in the development of MM, it may be used to evaluate disease progression, therapeutic curative effect and prognosis; (2) Telomerase activity is expressed in the proliferation period of MM cells. Telomerase activity is correlated with cell cycle.