Survival Of Multiple Myeloma Patients Research Articles

Frequent upregulation of G9a promotes RelB-dependent proliferation and survival in multiple myeloma

BackgroundMultiple myeloma is an incurable hematological malignancy characterized by a heterogeneous genetic and epigenetic landscape. Although a number of genetic aberrations associated with myeloma pathogenesis, progression and prognosis have been well characterized, the role of many epigenetic aberrations in multiple myeloma remain elusive. G9a, a histone methyltransferase, has been found to promote disease progression, proliferation and metastasis via diverse mechanisms in several cancers. A role for G9a in multiple myeloma, however, has not been previously explored.MethodsExpression levels of G9a/EHMT2 of multiple myeloma cell lines and control cells Peripheral Blood Mononuclear Cells (PBMCs) were analyzed. Correlation of G9a expression and overall survival of multiple myeloma patients were analyzed using patient sample database. To further study the function of G9a in multiple myeloma, G9a depleted multiple myeloma cells were built by lentiviral transduction, of which proliferation, colony formation assays as well as tumorigenesis were measured. RNA-seq of G9a depleted multiple myeloma with controls were performed to explore the downstream mechanism of G9a regulation in multiple myeloma.ResultsG9a is upregulated in a range of multiple myeloma cell lines. G9a expression portends poorer survival outcomes in a cohort of multiple myeloma patients. Depletion of G9a inhibited proliferation and tumorigenesis in multiple myeloma. RelB was significantly downregulated by G9a depletion or small molecule inhibition of G9a/GLP inhibitor UNC0642, inducing transcription of proapoptotic genes Bim and BMF. Rescuing RelB eliminated the inhibition in proliferation and tumorigenesis by G9a depletion.ConclusionsIn this study, we demonstrated that G9a is upregulated in most multiple myeloma cell lines. Furthermore, G9a loss-of-function analysis provided evidence that G9a contributes to multiple myeloma cell survival and proliferation. This study found that G9a interacts with NF-κB pathway as a key regulator of RelB in multiple myeloma and regulates RelB-dependent multiple myeloma survival. G9a therefore is a promising therapeutic target for multiple myeloma.

The effect that β-lactam antibiotics have on progression free and overall survival in multiple myeloma patients undergoing autologous stem cell transplantation.

e20518 Background: Gut microbiome dysbiosis is correlated with graft-versus-host disease (GVHD) in allogeneic stem cell transplant (allo-SCT) patients. In the allo-SCT population, antibiotics have been associated with increased risk for GVHD mortality and relapse due to loss of gut obligate anaerobes . It has been shown that antibiotics may negatively impact the efficacy of checkpoint inhibitors for patients with solid tumors. Based on these studies, we performed a retrospective analysis to determine if antibiotic treatment affects outcomes of multiple myeloma (MM) patients after autologous SCT (ASCT). Methods: This is a single institution retrospective study at Hackensack University Medical Center. A list of consecutive MM patients treated from 1/2012 to 12/2015 was obtained and an electronic medical record review of the first 217 who received ASCT was performed. Baseline characteristics, treatment history, transplant course and antibiotic treatment (including β-lactams, fluoroquinolones, macrolides, metronidazole, and vancomycin) were reviewed. Prophylactic antibiotics were excluded. Response was defined using the IMWG criteria. Median progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Log rank tests were used to compare the difference in survival between stratified groups. The LASSO cox regression analysis method was used for multivariate analyses of PFS and OS. Results: Of the 217 patients, 205 patients were available for analysis. Median age at ASCT was 61. β-lactams were associated with decreased median PFS (1.95 vs 4.77 years (yrs), p < 0.01) and decreased median OS (7.51 vs 13.45 yrs, p = 0.01). Multivariate analysis adjusting for lasso-selected age, gender, complete remission (CR) after ASCT, and ISS demonstrated independent progression risk associated with β-lactam use (HR = 2.00, 95% CI, 1.28–3.12, p < 0.01). β-lactams were associated with worse OS in multivariate analysis adjusting for lasso-selected age, gender, CR after ASCT and high risk cytogenetics (HR = 1.89, 95% CI, 1.07–3.40, p = 0.03). Conclusions: In this preliminary study, β-lactams predicted for decreased PFS and OS compared to patients who did not receive β-lactams in MM patients undergoing ASCT. The study was limited by its retrospective nature but demonstrates one of the first evaluations of antibiotic effect on the ASCT population in MM. Prospective studies evaluating the impact of antimicrobials on patient outcomes and the gut microbiome are ongoing.

Efficacy and tolerability of elotuzumab-based three-drug regimens for high-risk multiple myeloma: A meta-analysis.

e20550 Background: Efficacy of elotuzumab (E) based regimens in high risk multiple myeloma (MM) (i.e, ISS stage II/III and t(4;14) or (del17p) has not been thoroughly investigated. The aim of this study was to assess the efficacy of E based 3-drug regimens compared to non-E based regimens in high risk MM. Methods: A systematic review of literature was done to identify randomized controlled trials (RCTs) which reported overall response rates (ORR), progression free survival (PFS) and overall survival (OS) of MM patients (pts) with E based 3-drug regimens. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS and OS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using RevMan v.5.3 to report the efficacy of E based 3-drug regimens. A random effects model was employed only when there was significant heterogeneity among studies ( > 40%, as assessed by I-squared). Results: After screening 604 studies, 04 RCTs were included (n = 986 patients). E was evaluated with lenalidomide (L), pomalidomide (P), bortezomib (B) and dexamethasone (d). ELd regimen was studied in 359, EPd in 60 and EBd in 77 pts. Total 496 pts were evaluated with E. Pooled analysis of E based 3-drug regimens showed improved PFS (HR 0.69, 95% CI 0.59-0.81; p < 0.00001, I2 = 0%) and ORR (OR 1.92, 95% CI 1.33-2.78; p = 0.0005; I2 = 25%) as compared to non-E 2-drug regimens. Relapsed/refractory MM pts (n = 456) also showed improved ORR in E vs non-E groups (OR 1.88, 95% CI 1.19-2.97; p = 0.007; I2 = 47%). Sub-group analysis showed 30% reduction in progression in high risk MM pts (HR 0.70, 95% CI 0.53-0.94; p = 0.02; I2 = 0%) and 31% in standard risk pts (HR 0.69, 95% CI 0.53-0.88; p = 0.003, I2 = 0%). OS showed 25% reduction in risk of death with E based regimens (HR 0.75, 95% CI 0.62-0.91; p = 0.004, I2 = 0%). E proved to be clinically safe across all patients (OR 1.10, 95% CI 0.78-1.57; p = 0.58; I2 = 71%). Conclusions: Elotuzumab based 3-drug regimens appear to abrogate high risk features in MM compared to 2 drug regimens.

Daratumumab-based three drug regimens for high-risk multiple myeloma: A meta-analysis.

e20549 Background: Efficacy of daratumumab (D) based regimens in high risk multiple myeloma (MM) (i.e, ISS stage II/III and t(4;14) or (del17p)) has not been thoroughly investigated. The aim of this study was to assess the efficacy of D based 3-drug regimens compared to non-D based regimens in high risk MM. Methods: A systematic review of literature was performed to identify randomized controlled trials (RCTs) which reported overall response rates (ORR) and progression free survival (PFS) of MM patients (pts) with D based 3-drug regimens. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using RevMan v.5.3 to report the efficacy of D based 3-drug regimens. A random effects model was employed only when there was significant heterogeneity among studies ( > 40%, as assessed by I-squared). Results: Screening of 604 studies yielded 04 RCTs (n = 2,234 pts). D was evaluated with lenalidomide (L), carfilzomib (C), bortezomib (B) and dexamethasone (d). DLd regimen was studied in 649, DCd in 312 and DBd in 240 pts. Total 1201 pts were evaluated with D. D based 3-drug regimens proved to be of improved efficacy versus non-D 2-drug regimens in the pooled analysis i.e., PFS (HR 0.46, 95% CI 0.33-0.63; p < 0.00001; I2 = 81%) and ORR (OR 2.83, 95% CI 2.06-3.88; p < 0.00001; I2 = 44%). Relapsed/refractory MM (n = 833) also showed improved ORR (OR 2.79, 95% CI 1.78-4.36; p < 0.00001; I2 = 62%). In high risk group, addition of D decreased the risk of progression to 42% (HR 0.58, 95% CI 0.39-0.85; p = 0.005; I2 = 3%). In standard risk pts, D decreased the risk of progression/death to 66% (HR 0.34, 95% CI 0.23-0.51; p < 0.00001; I2 = 74%). D increased the risk of neutropenia (OR 1.88, 95% CI 1.54-2.31; p < 0.00001; I2 = 0%), respiratory tract infections (OR 1.87, 95% CI 1.49-2.35; p < 0.00001; I2 = 0%) and diarrhea (OR 1.83, 95% CI 1.46-2.29; p < 0.00001; I2 = 23%) in the study population. Conclusions: Daratumumab based 3-drug regimens appear to abrogate high risk features in MM compared to 2 drug regimens.

Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma.

Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.

Prediagnosis dietary pattern and survival in patients with multiple myeloma.

Inflammation and endogenous growth factors are important in multiple myeloma (MM) pathogenesis. Although diets that modulate these biologic pathways may influence MM patient survival, studies have not examined the association of dietary patterns with MM survival. We conducted pooled prospective survival analyses of 423 MM patients from the Nurses' Health Study (1986-2016) and the Health Professionals Follow-up Study (1988-2016) using Cox regression models. We used data from repeated food frequency questionnaires (FFQ) to compute dietary patterns as of the last prediagnosis FFQ, including the Alternate Healthy Eating Index (AHEI)-2010, alternate Mediterranean Diet, Dietary Approaches to Stop Hypertension, Prudent, Western and empirical dietary inflammatory patterns and empirical dietary indices for insulin resistance and hyperinsulinemia. During follow-up, we documented 295 MM-related deaths among 345 total deaths. MM-specific mortality was 15-24% lower per one standard deviation (SD) increase (e.g., toward healthier habits) in favorable dietary pattern scores. For example, the multivariable-adjusted hazard ratio [HR] and 95% confidence interval [CI] per 1-SD increase in AHEI-2010 score were 0.76, 0.67-0.87 (p < 0.001). In contrast, MM-specific mortality was 16-24% higher per 1-SD increase (e.g., toward less healthy habits) in "unhealthy" diet scores; for example, the multivariable-adjusted HR, 95% CI per 1-SD increase in Western pattern score were 1.24, 1.07-1.44 (p = 0.005). Associations were similar for all-cause mortality. In conclusion, our consistent findings for multiple dietary patterns provide the first evidence that MM patients with healthier prediagnosis dietary habits may have longer survival than those with less healthy diets.

Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines.

Approximately 20% of multiple myeloma (MM) cases harbor a point mutation in KRAS. However, there is still no final consent on whether KRAS-mutations are associated with disease outcome. Specifically, no data exist on whether KRAS-mutations have an impact on survival of MM patients at diagnosis in the era of novel agents. Direct blockade of KRAS for therapeutic purposes is mostly impossible, but recently a mutation-specific covalent inhibitor targeting KRASp.G12C entered into clinical trials. However, other KRAS hotspot-mutations exist in MM patients, including the less common exon-4 mutations. For the current study, the coding regions of KRAS were deep-sequenced in 80 newly diagnosed MM patients, uniformely treated with three cycles of bortezomib plus dexamethasone and cyclophosphamide (VCD)-induction, followed by high-dose chemotherapy and autologous stem cell transplantation. Moreover, the functional impact of KRASp.G12A and the exon-4 mutations p.A146T and p.A146V on different survival pathways was investigated. Specifically, KRASWT, KRASp.G12A, KRASp.A146T, and KRASp.A146V were overexpressed in HEK293 cells and the KRASWT MM cell lines JJN3 and OPM2 using lentiviral transduction and the Sleeping Beauty vector system. Even though KRAS-mutations were not correlated with survival, all KRAS-mutants were found capable of potentially activating MEK/ERK- and sustaining PI3K/AKT-signaling in MM cells.

Continued Improvement in Survival of Multiple Myeloma Patients: An Institutional Study from 1992-2016

Introduction Multiple myeloma (MM) represents 1.8% of all new cancer cases in the U.S. While not curable, advances in treatment, including autologous stem cell transplant (ASCT) and maintenance therapy, have dramatically improved progression free survival (PFS) and overall survival (OS). The Ohio State University began utilizing ASCT for newly diagnosed MM (NDMM) patients in 1992. With the introduction of new, more effective drugs used before and after ASCT over time, we performed retrospective survival analysis in NDMM patients receiving ASCT from 1992-2016. Method Consecutive 1002 NDMM patients were eligible. Patients were split into five groups based on historic changes in novel agents for treatment of MM: 1992-1998-group 1, 1999-2002-group 2, 2003-2008-group 3, 2009-2013-group 4, and 2014-2016-group 5. Pre-ASCT conditioning regimen was melphalan, 140 or 200 mg/m2. High-risk patients had del17, t(4:14), t(14:16), and/or 1q abnormality. Primary endpoints were PFS and OS. Kaplan Meier curves were used to calculate PFS and OS. Results Across the years (1992-2016), there was a statistically significant improvement in both PFS (p 65 years old, there was a statistically significant improvement in PFS (p Conclusion Survival since 1992 have improved primarily due to inclusion of novel therapies and maintenance. For NDMM patients receiving ASCT, the 3 year overall survival rate has significantly improved from 45% in 1992-1998 to 80% in 2014-2016, which is similar to the post-ASCT OS shown in the 2012 study by McCarthy et al. The significantly increasing age of NDMM patients receiving ASCT over time suggests improvement in supportive care and tolerability of current therapies.

Equivocal Significance of Prior Malignancies to Predict Overall Survival of Multiple Myeloma Patients after Autologous Hematopoietic Cell Transplant

Introduction Hematopoietic cell transplantation (HCT)-specific comorbidity index (Sorror et al. Blood 2005) is highly recommended by National Marrow Donor Program as a risk assessment tool before HCT. Prior malignancies has one of the highest weighted score of 3 in this risk model. The isolated prognostic value of prior malignancies has not been evaluated in Multiple Myeloma (MM) patients (pts) who underwent autologous HCT (AHCT) in large databases. We hereby used national cancer database (NCDB) to evaluate this. Methods NCDB covers more than 70% of newly diagnosed cancer pts in the U.S. We reviewed NCDB, using ICD-O code of 9732, to identify pts who were diagnosed with MM between 2010 and 2014, underwent systemic treatment within 90 days of the diagnosis, and subsequently AHCT. Prior malignancy was not incorporated into Charlson comorbidity index at NCDB and reported separately. Average annual volume of a cancer center for MM is calculated among pts who met the inclusion criteria. Overall survival (OS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Cox hazard analysis was performed to identify independent predictors of OS. Results We reviewed 12,427 pts and included 4358 pts who met inclusion criteria. Of which, 2481 (57%) were male, 693 (16%) were black, and 412 (10%) had at least one malignancies prior to MM. Median age at the diagnosis and time to initiation of systemic treatment after the diagnosis were 60 years (range: 25 – 80) and 17 days (range: 1 – 90), respectively. The Charlson comorbidity index was 0, 1, and ≥2 for 3646 (84%), 558 (13%), 154 (3%) pts, respectively. Durie-Salmon stage (DSS) at diagnosis was 1, 2, and 3 for 562 (13%), 1040 (24%), 2756 (63%) pts, respectively. Patient and treatment characteristics are compared between prior and no prior malignancy cohorts in table 1. Median follow-up time of pts was 36 months. Five-year OS of MM pts with and without prior malignancies was 75.6% (95% CI: 69.6 – 82.2) and 73.9% (95% CI: 71.6 – 76.2), respectively (p = 0.7) (Figure 1A). On multivariable analysis, each 10-year increase in age (HR 1.14, 95% CI: 1.02 – 1.26, p = 0.017), each 1 increase in comorbidity index (HR 1.24, 95% CI: 1.08 – 1.42, p=0.002) and year of MM diagnosis (HR 1.15, 95% CI: 1.06 – 1.24, p = 0.0008), DSS 3 vs 1 or 2 (HR 1.38, 95% CI: 1.16 – 1.64, p=0.0002), immunotherapy prior to AHCT (HR 0.72, 95% CI: 0.61 – 0.86, p = 0.0001), and each 10 increase in annual AHCT volume of a cancer center for MM (HR 0.98, 95% CI: 0.97 – 0.99, p = 0.016) were independent predictors of OS (Table 2). Conclusion In this large cohort analysis, prior malignancy was not a predictor of OS for MM pts who underwent AHCT. The role of prior malignancies in defining transplant eligibility requires future evaluation and the weighted value of this item in the comorbidity index should be considered for downward revision.

CAR-T cells in multiple myeloma: current status

SummaryStarting with the approval of bortezomib, a proteasome-inhibiting drug, tremendous progress has been achieved in the treatment of multiple myeloma (MM) patients during the last 15 years. Due to a plethora of novel drugs such as second generation proteasome inhibitors, immunomodulating agents and monoclonal antibodies the 5‑year survival of MM patients has been extended from 33% at the turn of the millennium to approximately 60% in younger patients (&lt;65–70 years) who were eligible for consolidation with high-dose chemotherapy and autologous stem cell transplantation. Unfortunately, virtually all patients suffer from relapse and ultimately succumb to the disease, indicating the need for additional treatment strategies. Currently there are two promising immunologic approaches. First, bispecific antibodies called BITE (bispecific T-cell enhancer), which act as fusion proteins with two single-chain variable fragments, target antigens on malignant cells and bind the CD3 receptor and thereby recruit T‑cells to the target cells. The second strategy is chimeric antigen receptor (CAR) engineered T‑cell therapy that attacks myeloma cells by recognizing specific targets such as CD138, BCMA (B-cell maturation antigen), light-chains, SLAM-F7 (signaling lymphocytic activation molecule family member 7) or the pan B‑cell antigen CD19.Several early phase clinical trials show encouraging results in patients who have relapsed after modern treatment including proteasome inhibitors, immunomodulating drugs and monoclonal antibodies. Here, we briefly summarize current clinical knowledge about CAR‑T cell treatment in multiple myeloma, including clinical data presented at the 61st American Society of Hematology annual meeting held in December 2019 in Orlando.

Construction of a prognosis‑associated long noncoding RNA‑mRNA network for multiple myeloma based on microarray and bioinformatics analysis.

At present, the association between prognosis-associated long noncoding RNAs (lncRNAs) and mRNAs is yet to be reported in multiple myeloma (MM). The aim of the present study was to construct prognostic models with lncRNAs and mRNAs, and to map the interactions between these lncRNAs and mRNAs in MM. LncRNA and mRNA data from 559 patients with MM were acquired from the Genome Expression Omnibus (dataset GSE24080), and their prognostic values were calculated using the survival package in R. Multivariate Cox analysis was used on the top 20 most significant prognosis-associated mRNAs and lncRNAs to develop prognostic signatures. The performances of these prognostic signatures were tested using the survivalROC package in R, which allows for time-dependent receiver operator characteristic (ROC) curve estimation. Weighted correlation network analysis (WGCNA) was conducted to investigate the associations between lncRNAs and mRNAs, and a lncRNA-mRNA network was constructed using Cytoscape software. Univariate Cox regression analysis identified 39 lncRNAs and 1,445 mRNAs that were significantly associated with event-free survival of MM patients. The top 20 most significant survival-associated lncRNAs and mRNAs were selected as candidates for analyzing independent MM prognostic factors. Both signatures could be used to separate patients into two groups with distinct outcomes. The areas under the ROC curves were 0.739 for the lncRNA signature and 0.732 for the mRNA signature. In the lncRNA-mRNA network, a total of 143 mRNAs were positively or negatively associated with 23 prognosis-associated lncRNAs. NCRNA00201, LOC115110 and RP5-968J1.1 were the most dominant drivers. The present study constructed a model that predicted prognosis in MM and formed a network with the corresponding prognosis-associated mRNAs, providing a novel perspective for the clinical diagnosis and treatment of MM, and suggesting novel directions for interpreting the mechanisms underlying the development of MM.

MicroRNA-146b overexpression associates with deteriorated clinical characteristics, increased International Staging System stage, cacoethic chromosome abnormality, and unfavorable prognosis in multiple myeloma patients.

BackgroundMicroRNA‐146b (miR‐146b) is a critical regulator and prognosis biomarker in several hematological malignancies, whereas its role in multiple myeloma (MM) was unclear. Therefore, this study aimed to investigate the significance of miR‐146b in MM patients.MethodsThe plasma cells were separated from bone marrow samples of 180 symptomatic MM patients (before treatment) and 50 healthy controls (HCs), and subsequently detected by reverse transcription‐quantitative polymerase chain reaction for miR‐146b expression.ResultsMiR‐146b was increased in MM patients compared with HCs (P < .001), and it predicted increased MM risk (area under curve (AUC): 0.879, 95% confidence interval (CI): 0.822‐0.936). For clinical parameters, miR‐146b was positively correlated with serum creatinine (P = .047), beta‐2‐microglobulin (P < .001), lactate dehydrogenase (P < .001), bone lesion (P = .027), International Staging System (ISS) stage (P < .001), and t (4; 14; P = .006), while negatively correlated with albumin (P = .004) in MM patients. For prognosis, miR‐146b was decreased in complete response (CR) patients compared with non‐CR patients (P = .025), as well as in overall response rate (ORR) patients compared with non‐ORR patients (P = .036), and it discriminated CR patients from non‐CR patients (AUC: 0.610, 95% CI: 0.523‐0.698) and distinguished ORR patients from non‐ORR patients (AUC: 0.602, 95% CI: 0.501‐0.703) in MM patients. Moreover, miR‐146b was correlated with worse progression‐free survival (P = .007) and overall survival (P = .014) in MM patients.ConclusionMiR‐146b was overexpressed in MM patients and predicted increased MM risk; meanwhile, it correlated with deteriorated clinical properties, increased ISS stage, cacoethic chromosome abnormality, and worse prognosis in MM patients.

Influence of applied CD34+ cell dose on the survival of Hodgkin's lymphoma and multiple myeloma patients following autologous stem cell transplants

Background/Aim. Autologous stem cell transplants (ASCTs) improve the rate of overall survival (OS) in patients with hematological malignancies such as multiple myeloma (MM) after induction chemotherapy, aggressive non-Hodgkin's lymphomas (NHL), and relapsed, chemotherapy- sensitive Hodgkin's lymphoma (HL). The study aim was to evaluate influence of applied CD34+ cell quantity on clinical outcome, as well as early post-transplant and overall survival (OS) of HL and MM patients following ASCT. Methods. This study included a total of 210 patients (90 HL/120 MM) who underwent ASCT. Stem cell (SC) mobilization was accomplished by granulocyte-colony stimulating factor (G-CSF) 10?16 ?g/kg body mass (bm) following chemotherapy. For proven poor mobilizers, mobilization with G-CSF (16 ?g/kgbm) and Plerixafor (24 or 48 mg) was performed. To our best knowledge, it was the first usage of the Plerixafor in our country in the ASCT-setting. Harvesting was initiated merely at "cut-off-value" of CD34+ cells ? 20 ? 106/L in peripheral blood with "target-dose" of CD34+ cells ? 5 ? 106/kgbm in harvest. The CD34+ cell count and viability was determined using flow cytometry. Results. The majority of HL patients (76.7%) were infused with &gt; 5.0 ? 106/kgbm CD34+ cells, while 68.3% of MM patients were treated by approximately 4.0?5.4 ? 106/kgbm CD34+ dose, respectively. Beneficial response (complete/ partial remission) was achieved in 83.3% (HL) and 94.2% (MM) patients. Among parameters that influenced survival of HL patients with positive response to the therapy, multivariate analysis (pre-ASCT performance status, CD34+ cell quantity applied, rapid hematopoietic, i.e. lymphocyte and platelet recovery) indicated that higher CD34+ cell dose used, along with pre-ASCT performance status correlated with superior event-free survival (EFS) and OS following ASCT. In MM patients, multivariate analysis (renal impairment, infused CD34+ cell quantity, early platelet recovery) indicated that the number of CD34+ cells infused was the most important parameter that influenced both EFS and OS after ASCT. Conclusion. Data obtained in this study undoubtedly confirmed that CD34+ cell dose applied is an independent factor that may contribute to superior clinical outcome and OS of HL and MM patients following ASCT.

Toll-like receptor CD180 and the bone marrow microenvironment as therapeutic targets in multiple myeloma

Multiple myeloma (MM) is among the most intractable of malignancies and is characterized by uncontrolled growth of malignant plasma cells in the bone marrow (BM). Elucidation of the mechanisms underlying cell adhesion-mediated drug resistance (CAM-DR) may prolong remission and ultimately improve the survival of MM patients. Toward this goal, we identified trimethylation of histone H3 at lysine-27 (H3K27me3) as a critical histone modification associated with CAM-DR. Cell adhesion counteracted drug-induced hypermethylation of H3K27 via inhibiting phosphorylation of enhancer of zeste homolog 2 (EZH2), and promoted sustained expression of anti-apoptotic genes. In addition, we found that CD180, a non-canonical lipopolysaccharide (LPS) receptor, was markedly up-regulated in response to adherence and/or hypoxic conditions. Bacterial LPS enhanced the growth of MM cells both in vitro and in vivo, correlating with expression of CD180. Promoter analyses identified Ikaros (IKZF1) as a pivotal transcriptional activator of the CD180 gene; expression of CD180 was activated via cell adhesion- and/or hypoxia-mediated increases in IKZF1 expression. Administration of lenalidomide prevented the LPS-triggered activation of MM cells by targeting CD180. Taken together, our results suggest that lenalidomide-mediated prevention of LPS-triggered disease progression may be an effective means for prolonging survival in patients with MM.

BRD4 inhibitor nitroxoline enhances the sensitivity of multiple myeloma cells to bortezomib in vitro and in vivo by promoting mitochondrial pathway-mediated cell apoptosis.

Background:Multiple myeloma (MM) is the second most common hematological neoplasm. Wide administration of bortezomib significantly improves the survival of MM patients compared with conventional chemotherapy. Bromodomain-containing protein 4 (BRD4) inhibitors also have been demonstrated to retard cell proliferation and induce cellular apoptosis in various cancers. However, it is unclear whether the BRD4 inhibitor nitroxoline plus bortezomib has a synergistic anti-tumor effect on MM.Methods:Cell viability was determined via 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle and cell apoptosis were assessed via flow cytometry. Protein expression levels were determined via western blotting. The expression of apoptosis-related proteins in xenograft tissue were detected by means of immunohistochemistry.Results:Treatment with nitroxoline or bortezomib suppressed cell proliferation, and caused G0/G1 phase arrest and apoptosis in H929 and RPMI8226 cells. Furthermore, nitroxoline intensified the retardation of cell proliferation, as well as further enhanced the G0/G1 phase arrest and apoptosis induced by bortezomib in H929 and RPMI8226 cells. The western blot analysis revealed that nitroxoline or bortezomib treatment markedly diminished the levels of Bcl-2 and cyclin D1, and increased the levels of p21, Bax, cleaved PARP and cleaved caspase-3. Combination of these two agents was observed to result in further marked changes on these levels compared with nitroxoline or bortezomib treatment alone. What is more, in the xenograft tumor model, combinative treatment markedly inhibited tumor growth compared with the single drug treatment.Conclusion:Combination of bortezomib with nitroxoline has a synergistic anti-tumor activity in MM cells and may be a novel treatment method for MM.

Data-Driven Statistical Modeling and Analysis of the Survival Times of Multiple Myeloma Cancer

Multiple Myeloma (MM) has been and continues to be the subject of many research studies. The main goal is to improve the therapeutic/treatment process of survival of MM patients. Based on the 2012-2016 MM cases and deaths, the number of new cases was 6.9 per 100,000 men and women per year, and the number of deaths was 3.3 per 100,000 men and women per year. It is therefore imperative to research into MM. In the present study, we proposed a data-driven statistical model for the survival time of 48 patients diagnosed with multiple myeloma as a function of 16 attributable risk factors. We identified 9 attributable risk factors out of 16 and one interaction term to be significantly contributing to the survival time. They are Bence Jone protein in urine, blood urea nitrogen (BUN)/serum creatinine, infections, % myeloid cells in peripheral blood, fractures, serum calcium, gender, platelets and age, and white blood cells & total serum protein an interaction term. The proposed model satisfied all the model assumptions, passes the residual analysis test and has very high prediction accuracy. Thus, it passes the goodnessof- fit test and the qualities of a good model. The identified significant attributable risk factors and the interaction has been ranked based on the percent contribution to the survival time. The proposed model was evaluated and compared with other existing models of survival of multiple myeloma. Our model is very accurate and also identifies some new significant risk factors. The study offers an improved strategy for the therapeutic/treatment process of multiple Myeloma Cancer.

Corrected estimated glomerular filtration rate is a predictor for survival in multiple myeloma patients

Corrected estimated glomerular filtration rate is a predictor for survival in multiple myeloma patients

Comorbidity and Personalized Treatment of Multiple Myeloma in Real Clinical Practice

Aim. To study incidence and structure of comorbidity in multiple myeloma (MM) patients depending on their age; to determine its effect on overall survival, efficacy, and safety of the first-line therapy in real clinical practice. Materials &amp; Methods. Overall, 369 patients with newly diagnosed MM were enrolled in the trial from January 2012 to December 2017. Among them there were 134 men and 235 women hospitalized at the Unit of Hematology in the Novosibirsk Municipal Clinical Hospital No. 2. Median age of patients was 67 years (range 32-82 years). Results. The analyzed patients were divided into three age groups: the first group of young/middle age (32-59 years) (n = 105), the second group of elderly patients (6074 years) (n = 186), and the third group of old age (&gt; 75 years) (n = 78). In each patient prior to chemotherapy the comorbidity spectrum was identified and CIRS-G, CCI, and MCI comorbidity scores were calculated. Patients with newly diagnosed MM in real clinical practice prove to have high and increasing with age comorbidity incidence (91 % in patients of young/middle age, 97,7 % and 100 % in patients of elderly and old age, respectively). Comorbidity significantly reduces overall survival (OS) of MM patients. Important OS predictors are rhythm and conduction disorder (odds ratio, OR, 2.762; p &lt; 0.002), chronic pancreatitis (OR 1.864; p &lt; 0.001), exogenous constitutive obesity (OR 1.948; p &lt; 0.002), chronic obstructive pulmonary disease (OR 2.105; p &lt; 0.021), chronic kidney disease, stage С4-С5 (OR 2.255; p &lt; 0.003), and chronic heart failure, functional class II (OR 1.915; p &lt; 0.002). Highest importance in predicting OS, efficacy, and tolerance to chemotherapy in MM patients is attached to MCI score (OR 3.771; p &lt; 0.001). MM patients with high risk by MCI are characterized by lower rate and depth of response to the first-line therapy, shorter time before the first relapse, higher incidence of non-hematologic toxicity of grade &gt; 3, and therapy withdrawal or drug dose reduction.

Repurposing old drugs as new inhibitors of the ubiquitin-proteasome pathway for cancer treatment.

The ubiquitin-proteasome system (UPS) plays a central role in the degradation of cellular proteins. Targeting protein degradation has been validated as an effective strategy for cancer therapy since 2003. Several components of the UPS have been validated as potential anticancer targets, including 20S proteasomes, 19S proteasome-associated deubiquitinases (DUBs) and ubiquitin ligases (E3s). 20S proteasome inhibitors (such as bortezomib/BTZ and carfilzomib/CFZ) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of multiple myeloma (MM) and some other liquid tumors. Although survival of MM patients has been improved by the introduction of BTZ-based therapies, these clinical 20S proteasome inhibitors have several limitations, including emergence of resistance in MM patients, neuro-toxicities, and little efficacy in solid tumors. One of strategies to improve the current status of cancer treatment is to repurpose old drugs with UPS-inhibitory properties as new anticancer agents. Old drug reposition represents an attractive drug discovery approach compared to the traditional de novo drug discovery process which is time-consuming and costly. In this review, we summarize status of repurposed inhibitors of various UPS components, including 20S proteasomes, 19S-associated DUBs, and ubiquitin ligase E3s. The original and new mechanisms of action, molecular targets, and potential anticancer activities of these repurposed UPS inhibitors are reviewed, and their new uses including combinational therapies for cancer treatment are discussed.

Clinical and Pharmacologic Features of Monoclonal Antibodies and Checkpoint Blockade Therapy in Multiple Myeloma.

Survival of multiple myeloma patients has considerably improved in the last decades thanks to the introduction of many new drugs, including immunomodulatory agents, proteasome inhibitors and, more recently, monoclonal antibodies. We analyzed the most recent literature focusing on the clinical and pharmacologic aspects of monoclonal antibody-based therapies in multiple myeloma, including monoclonal antibodies directed against plasma cell antigens, as well as checkpoint blockade therapy directed against immune inhibitory molecules, used as single agents or in combination therapy. Anti-CD38 monoclonal antibodies including daratumumab, isatuximab and MOR202 have shown outstanding results in relapsed and/or refractory multiple myeloma patients. The addition of daratumumab to bortezomib-dexamethasone or lenalidomidedexamethasone substantially improved patients' outcome in this patient population. The anti- SLAMF7 molecule elotuzumab in combination with lenalidomide-dexamethasone showed to be superior to lenalidomide-dexamethasone alone, without adding meaningful toxicity. Checkpoint blockade therapy in combination with immunomodulatory agents produced objective responses in more than 50% of treated patients. However, this combination was also associated with an increase in toxicity and a thorough safety evaluation is currently ongoing. Monoclonal antibodies are reshaping the standard of care for multiple myeloma and ongoing trials will help physicians to optimize their use in order to further improve patients' outcome.