Higher International Staging System Research Articles

PHF19 before and post induction treatment possess favorable potency of reflecting treatment response to protease inhibitors, event-free survival, and overall survival in multiple myeloma patients

ABSTRACT Objective Plant homeodomain finger protein 19 (PHF19) regulates hematopoietic stem cell differentiation and promotes multiple myeloma (MM) progression. This study intended to explore the potency of PHF19 at baseline and post induction treatment in estimating treatment response to protease inhibitors and survival in MM patients. Methods This retrospective study screened 69 MM patients who received protease inhibitors with bone marrow (BM) samples available at both baseline and post induction treatment. Twenty healthy BM donors were included as healthy controls (HCs). PHF19 in plasma cells from BM was quantified by reverse transcription-quantitative polymerase chain reaction. Results PHF19 at baseline and post induction treatment in MM patients were increased than in HCs. In MM patients, PHF19 was declined post induction treatment. Elevated PHF19 at baseline and post induction treatment were correlated with renal impairment, beta-2-microglobulin ≥5.5 mg/L, t (4; 14), higher international staging system (ISS) stage, and higher revised ISS (R-ISS) stage. Concerning treatment response, PHF19 at baseline and post induction treatment were negatively associated with complete response and overall response rate. Notably, abnormal PHF19 (above 95% quantile value of PHF19 in HCs) at baseline and post induction treatment were linked with shortened event-free survival (EFS) and overall survival (OS). After adjustment, abnormal PHF19 post induction treatment was independently related to shortened EFS (hazard ratio = 2.474) and OS (hazard ratio = 3.124). Conclusion PHF19 is aberrantly high and declines post induction therapy, which simultaneously reflects unfavorable treatment response to protease inhibitors as well as shorter EFS and OS in MM patients.

Improved survival in myeloma patients-a nationwide registry study of 4,647 patients ≥75 years treated in Denmark and Sweden.

The prevalence of multiple myeloma (MM) is increasing in Nordic countries and the rest of the western world. Patients aged ≥75 years at diagnosis constitute an increasing proportion of all MM patients, but are underrepresented in randomized clinical trials. There is an urgent need for studies of the characteristics, treatment and outcome in this cohort. We present data from two nationwide population-based registries of all MM patients diagnosed in Denmark from January 1, 2005 until February 18, 2020, and in Sweden from January 1, 2008 until December 31, 2019, including treatment data for patients diagnosed until 2018 (Denmark) and 2019 (Sweden). In total 4,647 patients were ≥75 years at diagnosis, compared to 7,378 younger patients. Patients ≥75 years, accounting for approximately 40% of all MM patients, are a distinct cohort with more advanced disease at diagnosis, reflected by higher International Staging System (ISS) stage, and a higher proportion have renal failure and anemia. We found a more gradual introduction of modern medications in the older cohort than in the younger, despite simultaneous changes in guidelines. Compared to the cohorts in randomized controlled trials that guide the treatment of non-transplant eligible patients, we found a higher proportion of patients ≥75 years and presenting with ISS III in the real-world populations. Nevertheless, response rates and survival are increasing, indicating that modern treatment regimens are effective and well tolerated also in elderly MM patients in real-world populations.

Integrative analysis of enrichment and prognostic value of ferroptosis-related genes and pathways in multiple myeloma.

Ferroptosis is a non-apoptotic form of cell death caused by excessive iron exposure. The role played by the ferroptosis-related genes and pathways in multiple myeloma (MM) is poorly understood. Here, we show that the ferroptosis-related pathways might be involved in tumorigenesis and are closely correlated with the prognosis of MM. The ferroptosis suppressor genes are progressively enriched with the progression of plasma cell dyscrasias. Furthermore, high expression of ferroptosis suppressor genes is correlated with high International Staging System and Revised-ISS staging of MM, as well as the poor outcomes of poor outcomes in progression-free survival and overall survival . The ferroptosis driver genes and the ferroptosis suppressor genes have the opposite effects on the progression and prognosis of MM. Moreover, we reveal that ferroptosis-related genes are associated with cytogenetic abnormalities in MM. The ferroptosis-related pathways and genes might impact the osteogenic differentiation of mesenchymal stromal cells in MM patients. A better understanding of the participation of ferroptosis in MM will pave the way for design of new therapies.

Ixazomib, lenalidomide, and dexamethasone combination in "real-world" clinical practice in patients with relapsed/refractory multiple myeloma.

Ixazomib is approved for use in combination with lenalidomide and dexamethasone (IRd) for patients with multiple myeloma (MM) who received at least one previous therapy. Registration study "TOURMALINE MM-1" was published in 2016. Nevertheless, clinical trials are significantly different from real-world use. From June 2016 to December 2018, IRd was available for Slovak patients with relapsed/refractory MM through a Named Patient Program. The aim of this study was to evaluate the efficacy and safety of ixazomib. We analyzed in this cohort study outcomes of 106 MM patients treated with IRd at 2 academic centers. The median age at diagnosis was 63years (44-78). The median number of prior lines was 2 (1-7). The majority had high international staging system (ISS) score: 18, 29, and 59 were in the ISS I, ISS II, and ISS III groups, respectively. Treatment continued until progression, unacceptable toxicity, or death. The median follow-up for the entire cohort was 29 (0-49) months. The overall response rate was 74.5% (complete remission, 7.5%; partial remission, 67%). The median overall survival was not reached. Median progression-free survival (PFS) was 43months (95% CI 35.6-50.4). The Kaplan-Meier method was used to generate survival curves, and we compared the influence of different factors on PFS. The most common hematological adverse events of any grade were neutropenia (90.4%), anemia (55.6%), and thrombocytopenia (43.4%). Our real-world data support the use of IRd as a highly effective and well-tolerated oral treatment protocol for relapsed myeloma.

PHD finger protein 19 expression in multiple myeloma: Association with clinical features, induction therapy outcome, disease progression, and survival.

BackgroundPHD finger protein 19 (PHF19), also known as polycomb‐like protein 3 (PCL3), promotes the progression of multiple myeloma (MM) and drug resistance; however, its role in the management of MM remains unclear. Therefore, we aimed to elucidate the correlation between PHF19 expression and treatment response, disease progression, and survival of patients with MM.MethodsPlasma cells derived from the bone marrow of 101 patients with de novo MM were collected prior to induction therapy, as were plasma cells derived from the bone marrow of 30 healthy donors. PHF19 expression in plasma cells was analyzed using quantitative reverse transcription polymerase chain reaction. Furthermore, the response to induction therapy, progression‐free survival (PFS), and overall survival (OS) were assessed.ResultsPHF19 expression tends to be upregulated more often in MM patients than in healthy donors (p < 0.001) and can accurately predict MM risk (area under curve [AUC], 0.916; 95% confidence interval [CI], 0.869–0.962). Furthermore, elevated PHF19 expression was correlated with higher International Staging System (ISS) (p = 0.036) and revised ISS stages (p = 0.035). In addition, MM patients who achieved complete response (CR) exhibited reduced PHF19 compared to those who did not (p = 0.028). Moreover, increased PHF19 expression was correlated with unfavorable PFS (p = 0.006) and OS (p = 0.027) rates. Furthermore, the results of multivariate Cox analysis also revealed that PHF19 high expression was independently associated with a reduced PFS rate (hazard ratio: 2.025, p = 0.028).ConclusionIncreased PHF19 expression is correlated with poor induction therapy response and unfavorable long‐term prognosis of MM.

Diagnostic Pathways of Myeloma Patients Presenting to Hospital Care and Relationship to End Organ Damage: An Analysis from the Teamm (Tackling EArly Morbidity and Mortality in Myeloma) Trial in 977 Patients

Introduction and methods: Myeloma is a cancer with one of the longest pathways to diagnosis. This may be due to the non-specific nature of presenting symptoms and its' relative rarity. Early diagnosis initiatives have focused on the role of the primary physician. Despite concern that patients referred to non-haematology specialists may experience long diagnostic intervals, data remain sparse on pathways within hospital care. The TEAMM trial is a double-blind, placebo controlled multicentre UK trial of supportive care, investigating levofloxacin prophylaxis for 12 weeks from diagnosis to reduce infection, versus the risk of healthcare associated infection. Data were collected from patients within 14 days of starting anti-myeloma treatment, including symptoms attributable to myeloma, visits to their primary physician, first hospital department visited for these symptoms, and first visit to a haematologist, with corresponding dates. The relationship between diagnostic time intervals and the number of CRAB (hyperCalcaemia, Renal disease, Anaemia, Bone disease) features and ISS (International Staging System) were analysed by pathway into hospital care using the chi-square test for categorical variables or Wilcoxon/Kruskal-Wallis test for continuous variables as appropriate.Results: Diagnostic pathway data were available for 915 patients. Table 1 presents baseline factors and diagnostic time intervals by the route to haematology. The largest group were those referred directly to haematology by their primary physician (n=468, 51%). 269 patients (29%) were ‘acute’ whose first hospital encounter was via the emergency services, although they were not necessarily diagnosed consequent upon the visit.178 patients (20%) were first referred to other departments. These patients experienced a longer diagnostic pathway (median 120d=days) than those first presenting via haematology clinics (median 59d) or emergency services (median 59d). A median of 30d intra-hospital delay contributed to this longer pathway. Table 2 lists the departments first visited. Two or more CRAB features were commonest in the ‘acute’ patients compared to the ‘haematology direct’ or ‘other route’ patients (52% vs 24% and 25%, p<0.0001). Patients presenting via other routes had a CRAB profile similar to that of the patients referred directly to haematology and significantly less severe than the acute patients (p<0.0001). Acute pathway patients were more likely to be ISS stage 3 compared to patients who entered directly to haematology, or via other routes (42% vs 21% and 29%, p<0.0001).Discussion : The 20% of patients who entered hospital care via ‘other routes’ have previously been inaccessible to analysis possibly because myeloma patients are median age >70 with frequent comorbidities, making registry data difficult to interpret. Recognising these unusual protracted paths to diagnosis may provide an opportunity for healthcare improvement. Our total diagnostic time intervals were shorter than previously reported in the UK. Our endpoint was the first visit to a haematologist ie prior to the date of histological diagnosis as used in previous studies. Patient recall for events may also underestimate the earliest date of symptom onset. Total diagnostic times may overall be longer than our figures but the subgroup comparisons remain valid.CRAB features were more common in ‘acute’ patients possibly reflecting more aggressive disease. The longer path to diagnosis in ‘other route’ patients may reflect a more indolent disease which is less easily recognised. The similarity between the CRAB profile of these and the haematology direct group versus the sicker acute patients suggests this may be the case but does not rule out missed healthcare opportunities. The relation between diagnostic time intervals and CRAB features needs to be explored further.Conclusion: Emergency patients had more CRAB features and higher ISS and PS (performance status) than other groups. First presentation via emergency services was common (29%), even in a relatively good PS group of trial patients. 20% of patients presented via non-haematological non-emergency specialities and experienced a longer time to diagnosis, and yet despite this they had a broadly similar CRAB profile to the haematology direct patients, who had been seen more promptly. Diagnostic pathways may reflect tumour biology and need further exploration. [Display omitted] DisclosuresBowcock:Celgene: Other: Educational support; Amgen: Honoraria; Takeda: Other: educational support. Yong:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

IgD Myeloma: Clinical Features and Outcome from a Multicenter Retrospective Study in Chinese and Korean of 308 Patients from Asian Myeloma Network (AMN) Project

IgD myeloma is a rare hematologic malignancy for which clinical and biological features and patient outcomes have not been extensively studied. However, previous studies found 3.1% IgD myeloma prevalence in Asian myeloma patients, and with the high incidence of 6%, especially for younger than 50 years with 10.3% in Chinese myeloma patients (Kim K. et al. Am J Hematol. 2014, Lu J. et al. Drug Des Devel Ther. 2016). Therefore, to further assess the frequency and the specific characteristics and evaluate the outcome of patients with IgD myeloma, we carried out a multicenter retrospective study in Chinese and Korean patients from AMN project with diagnosis of IgD myeloma.A total of 308 patients from 22 centers were included in this analysis. The median age at diagnosis was 56 years with a male predominance (65.70%). Anemia and renal dysfunction were found in 86.7% and 46.2%, respectively. Renal failure is more common at presentation with an increase in serum creatinine (> 2 mg/dL) in more than 10% various series of IgD MM. The bias for λ light chain expression with a reversed light chain ratio is a characteristic feature of IgD MM, which showed 95.79% of patients with IgD λ light chain in Asian patients. DS stage 1, 2, and 3 were showed in 1.30%, 5.84%, and 92.86%, respectively. The chromosomal aberration accounted in 58.14% and t(11;14) was the most common cytogenetic finding (40.57%). Median overall survival (OS) was 39.2 months (95% CI 31.56-41.43). Higher International Staging System (ISS) stages III (62.62%) might be associated with worse survival (P = 0.02), while ISS stages I and II were seen in 16.39% and 20.98%. Patents received with stem cell transplantation showed better survival rates. New drugs including bortezomib, thalidomide, and lenalidomide were used in more than 60% of all patients and affected OS when used as a first-line treatment.In this multicenter retrospective study from Chinese and Korean IgD myeloma patients, we found that IgD MM more likely presented at advanced stage and showed a more aggressive clinical course. The underlying tumor biology responsible for these differences remains to be determined. DisclosuresNo relevant conflicts of interest to declare.

Predictors of Healthcare Utilization in Newly Diagnosed Myeloma

Introduction The introduction of novel therapies has significantly improved outcomes in myeloma. However, the economic burden of enhanced healthcare utilization is significant and cannot be discounted. This study sought to identify baseline characteristics that may influence outcomes and subsequent healthcare utilization. Patients were also stratified by induction therapy to determine the impact newer combinations have on healthcare utilization. Methods This retrospective single-center study enrolled all newly diagnosed patients with myeloma between 2005 and 2020. Three outcome measures were used to determine healthcare utilization - total inpatient length of stay (LOS), number of admissions, and day ward attendances. Univariate and multivariable analyses were performed to identify significant covariates related to overall survival (OS) and healthcare utilization. Outcomes were subsequently adjusted for duration of follow-up and per patient year. Results There were 113 patients included; 60 (53.1%) female; median age at diagnosis was 67 years (IQR 62, 73 years) and 22.1% were high risk International Staging System (ISS). Further baseline demographics are presented in Table 1. Median duration of follow up was 3.2 years (IQR 1.50, 6.55). Sixty patients (53.1%) died, 91.7% attributable to myeloma or its treatment. Predictors of OS by multivariable analysis were advanced stage [ISS III (p&amp;lt;0.001)] and IgA idiotype [(IgA vs IgG) (p=0.0002)]. Stem cell transplant eligibility was associated with improved OS (p=0.003). The total number of admissions to hospital was 547 (median 4; IQR 2, 7), with 55.4% unplanned. In the multivariable analysis, younger age (p=0.020), higher paraprotein levels (p=0.045), dialysis (p=0.037), and SCT eligibility (p=0.0012) were predictive of greater number of admissions. During the study period, there were 7000 inpatient bed occupancy days (median 46; IQR 26, 80). Only younger age remained significant (p=0.0028) in the multivariable analysis. There were a total of 5987 day care attendances during the study period. Multivariable analysis identified younger age at diagnosis (p&amp;lt;0.0001), WBC (p=0.0072), and light chain (kLC vs lLC) (p=0.0027) as predictive of increased day ward attendance. Healthcare utilization correlated with increased survival, as depicted in figure 1. There was no significant relationship between treatment type and LOS (p=0.055); this remained unchanged when adjusted per patient year (p=0.24). There was significant relationship between treatment type and total number of admissions (p=0.015). Patients receiving anthracycline based therapy (p=0.003), Immunomodulatory (IMiD)/Proteasomal Inhibition (PI)/Steroid (p=0.020), or PI/Steroid (p=0.021) were more likely to have a greater number of admissions. However, when adjusted per patient year, this association was no longer evident (p=0.19). A highly significant relationship between treatment type and day ward attendances was identified (p&amp;lt;0.0001). Alkylator based (pp=0.005), alkylator/PI/Steroid (p=0.006), anthracycline based (p=0.0002), IMiD/PI/Steroid (p=0.0007), or PI/Steroid (0.0002) were more likely to have greater day ward attendance. When adjusted per patient year, this significant association between treatment type and day ward attendance remained (p=0.0002). Conclusion Studies assessing healthcare utilization in patients with myeloma are mostly limited to relapsed refractory setting. In this population, younger age at presentation was a significant predictor for all three measures of healthcare utility. Whilst treatment type did not demonstrate a significant impact of LOS, we did determine that novel triplet therapy combinations were associated with increased number of admissions and day care attendances. We also showed that healthcare utilization increased with survival time. While survival outcomes with novel agents have improved, given current financial and capacity limitations within which the majority of health systems function, resource demand implications must be considered when planning future service provision and novel treatment strategies. Disclosures No relevant conflicts of interest to declare.

Racial differences in treatment and outcomes in multiple myeloma: a multiple myeloma research foundation analysis

Findings on racial differences in survival in multiple myeloma (MM) have been inconclusive. We assessed differences in outcomes between White and Black individuals among 639 newly diagnosed MM patients in the MM Research Foundation CoMMpass registry with baseline cytogenetic data. Survival curves were constructed using the Kaplan–Meier method. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazard regression models. Age, gender, and stage were similar between Whites (n = 526) and Blacks (n = 113). Blacks had inferior overall survival (OS) compared with Whites and were less likely to receive triplet therapies or frontline autologous stem cell transplant (ASCT). The following factors were significantly associated with inferior OS in multivariate analysis: higher international staging system (ISS) score, ≥1 or ≥2 high-risk cytogenetic abnormalities (HRCA), high-risk gene expression profile (GEP), and lack of ASCT. Multivariate analysis in the Black subset found that only lack of ASCT was significantly associated with inferior OS. The receipt of both triplet induction and ASCT only partly abrogated the effect of race on survival. HRCA did not track with survival in Blacks, emphasizing the need for race-specific risk prognostication schema to guide optimal MM therapy.

Early monoclonal protein decline pattern is an independent prognostic factor in patients with multiple myeloma.

Patients always have different responses to the same treatment due to the heterogeneity of multiple myeloma (MM). However, the relationship between monoclonal protein (M-protein) reduction rates during treatment and survival prognosis in MM patients remains controversial. We retrospectively analyzed 198 newly diagnosed MM patients who received regular bortezomib-based chemotherapy for at least 2cycles and subsequent autologous stem cell transplantation (ASCT) plus continuous maintenance. The relationship between the early M-protein reduction rates and survival prognosis was evaluated. This study is the first to divide patients into three patterns, namely, A, B, and C, according to the M-protein reduction rate during the first two therapy cycles. The results showed that pattern B patients with progressive reduction in M-protein had better progression-free survival (PFS) and overall survival (OS) than did pattern A or C patients with precipitating or slow M-protein reduction (75.33 ± 18.81 versus 41.23 ± 9.13 or 26.60 ± 6.67months; P < 0.001; 117.33 ± 18.44 versus 71.00 ± 10.06 or 39.73 ± 24.10months; P = 0.003, respectively). In addition, biological analysis showed that pattern A + C patients had higher international staging system (ISS) stage III proportions (P = 0.008) and lactate dehydrogenase (LDH) elevations (P = 0.044) than pattern B patients. Furthermore, pattern A + C was a significant independent adverse parameter for PFS and OS (HR = 2.62, P = 0.001; HR = 2.15, P = 0.022, respectively). Thus, our results demonstrate that pattern A + C indicates an inferior survival prognosis in MM.

Protein Kinase D 1 Predicts Poor Treatment Response and Unfavorable Survival of Bortezomib-Based Treatment, and Its Knockdown Enhances Drug Sensitivity to Bortezomib in Multiple Myeloma.

Objective:The present study aimed to explore the correlation of protein kinase D 1 with prognosis in bortezomib-treated multiple myeloma patients and further investigate the effect of protein kinase D 1 knockdown on drug sensitivity to bortezomib in multiple myeloma cells.Methods:Totally, 104 de novo symptomatic multiple myeloma patients treated with bortezomib-based regimens and 30 healthy controls were recruited. Bone marrow mononuclear cells–derived plasma cells were collected from multiple myeloma patients before initial treatment and from healthy controls on the bone marrow donation, respectively, then protein kinase D 1 protein/messenger RNA expressions were detected by Western blot and reverse transcription quantitative polymerase chain reaction, respectively. The effect of protein kinase D 1 knockdown on drug sensitivity to bortezomib was detected by transfecting protein kinase D 1 knockdown plasmid and control plasmid into RPMI8226 and U266 cells.Results:Protein kinase D 1 protein/messenger RNA expressions were both upregulated in multiple myeloma patients compared with healthy controls and presented good value in differentiating multiple myeloma patients from healthy controls. Furthermore, protein kinase D 1 protein/messenger RNA expressions were both associated with high International Staging System stage and t (4; 14). Furthermore, both complete response rate and overall response rate were reduced in protein kinase D 1 high patients compared with protein kinase D 1 low patients; similarly, progression-free survival and overall survival were both decreased in protein kinase D 1 high patients compared with protein kinase D 1 low patients. In addition, in RPMI8226 and U266 multiple myeloma cells, protein kinase D 1 knockdown increased drug sensitivity to bortezomib.Conclusion:Protein kinase D 1 has the potential to predict poor treatment response and unfavorable survival of bortezomib-based treatment in multiple myeloma patients, and its knockdown enhanced drug sensitivity to bortezomib in multiple myeloma cells.

What are the factors affecting survival after autologous stem cell transplantation in patients with multiple myeloma?

Introduction: High-dose chemotherapy (HDC) and autologous stem cell transplantation(ASCT) still remains in the treatment of myeloma patients even during the period of new agents. Materials and Methods: We analysed the prognostic affect of pretransplant characteristics and transplant modalities on response, in 150 autologous transplant of 144 multiple myeloma (MM) patients who were transplanted in our centre between 2008 to 2017. We evaluated the affect of age, type of MM, previous treatment regimens, status pre and postfrom transplantation, time of ASCT, neutrophil and platelet engraftmant days, dose of reinfused CD34+ cells, plasma cell infiltration, international staging system(ISS) and Durie -Salmon stage at diagnosis. We examined the affect of these status on overall survival(OS) and eventfree survival(EFS). Results: The median OS and EFS after transplanation were 41 and 28 months, respectively. Median OS after the diagnosis was 57 months. Transplant-related mortality was 3,3%. We found that the lower β2- microglobulin levels,lower ISS stage,lower plasma cell infiltration, achievement good responds at the +100th day of post transplant were statistically significant independent predictor factors for longer EFS and OS. When the patients were given chemotherapy regimen with bortezomib before transplantation, these patients were seen to be a better response rate. There was showed a relationship between the using of bortezomib before transplantation with EFS(P = 0.017), but there was no relationship with OS. Conclusions: Our analysis confirms HDCT-ASCT as an effective and safe therapeutic strategy in multiple myeloma patients. This results were independent of age, first line treatment regimens and renal insufficiency. Patients with a high ISS stage were found to have shorter survival(P = 0.002). However, the EFS and OS were longer of the patients whose have good response at the 100th day of transplantation(P = 0,002, P = 0,02).

Age Is a Prognostic Factor for the Overall Survival of Patients with Multiple Myeloma Undergoing Upfront Autologous Hematopoietic Stem Cell Transplantation.

In this retrospective analysis, we evaluated the impact of age on the outcome of patients with multiple myeloma who received an autologous hematopoietic stem cell transplantation (auto-HCT) at our institution. A total of 1128 patients were divided into the older (>70 years; 182 [16%]) and the younger (≤70 years; 946 [84%]) groups. Compared with the younger cohort, older patients had a higher International Staging System (ISS) stage (ISS-II, 57 [31%] versus 215 [23%]; ISS-III, 52 [28%] versus 211 [22%]; P=.01), higher use of reduced-dose melphalan as a conditioning regimen (140 mg/m², 59 [32%] versus 29 [3%]; P < .001), and a higher comorbidity index (median, 3 versus 2; P=.01). Nonrelapse mortality at 1 year after auto-HCT was significantly higher in older patients (7 [4%] versus 9 [1%]; hazard ratio [HR], 4.1; P=.005). Complete remission rates after auto-HCT for the older and the younger groups were 41% and 46%, respectively. With a median follow-up of 52 months, the 5-year progression-free survival (PFS) was 24% (95% confidence interval [CI], 17% to 32%) and 37% (95% CI, 33% to 40%) in the older and younger groups, respectively (HR, 1.3; P=.02). Five-year OS for the older and younger groups was 56% (95% CI, 47% to 64%) and 73% (95% CI, 70% to 76%; P < .001), respectively. Older age emerged as one of the predictors of shorter OS but not PFS in the multivariate classification and regression tree analysis. In conclusion, age ≥70 years was associated with shorter PFS and OS in patients with multiple myeloma who underwent an auto-HCT.

Characterization of Circulating and Bone Marrow Derived Exosomes in Multiple Myeloma Patients

Background: Multiple myeloma (MM) is characterized by clinical and biological heterogeneity, translating to variable outcome. High International Staging System (ISS), high risk cytogenetics, elevated LDH, poor response to novel drugs or extramedullary-disease (EMD) are associated to poor prognosis. Exosomes (EXO) are extra vesicular particles implicated in intercellular communication. Exosomal cargo has recently been studied as prognostic factors in cancer. MM-EXO may act as biomarkers of disease aggressiveness and potentially be used for better stratification of high risk disease in the clinical setting as liquid biopsies.Aims: To characterize peripheral blood (PB) and bone marrow aspirates (BM) EXO in MM and MGUS patients versus healthy donors (HD) and to analyze its potential use as a prognostic biomarker.Methods: EXO were isolated from PB and BM samples by ultracentrifugation. EXO protein quantity (EXOcargo) was determined by the ratio between total quantity of proteins and the total number of exosomes. Comparisons among groups of patients (MM, MGUS) and HD were made regarding EXO total protein cargo (PB and BM).Results: MM patients revealed 5x times higher EXOcargo in PB (ug/EXO) when compared to MGUS patients (p=0.007, n=15 MM and n=8 MGUS); MM median 2.34 (1.08-6.5) ug/EXO versus MGUS median 0.51 (0.29-1.04) ug/EXO. There was no differences regarding the EXOcargo between the MGUS and HD (n=6, HD median 0.88 (0.57-1.83)ug/EXO). In BM, MM EXOcargo was also higher than in MGUS: MM 2.09 (0.49-3.85)ug/EXO versus MGUS 0.53 (0.21-0.831)ug/EXO. Analyzing the patients with higher EXOcargo, we found that patients with EMD (n=4) are among the ones with higher circulating exosomal protein cargo (median 5.76 (4.36-7.95). A positive correlation in EXOcargo between PB and BM in MM and MGUS (Spearman r=0.85; p< 0.0001) was found. We also studied circulating EXOcargo at response evaluation (T2) compared to EXOcargo before MM treatment (T1): patients with deeper response had significant lower EXOcargo (CR T2 median 0.85 (0.65-1.35) p<0,05); patients in VGPR (T2 median 1.52 (0.86-2.34) p=0.36) PR (T2 median 2.68 (2.03-3.33) p=0.94) and progression (T2 median 2.22 (1.0-2.46) p=0.58).Conclusion: 1-The positive correlation of the exosomal protein cargo in PB and BM samples may be a reflection of the BM compartment and potentially supports the use of EXO as liquid biopsies for biomarkers of BM disease, in a less invasive method. 2-MM patients have higher circulating exosomal protein cargo in PB when compared to MGUS patients and HD. 3- Patients with extramedullary disease and more aggressive forms of multiple myeloma have a higher exosomal cargo in the PB and this might be related to different biological features of the disease. The longitudinal evaluation in 2 different time-points suggests a correlation between EXO protein cargo and response to treatment, to be confirmed in a larger cohort. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Real World Data on the Efficacy and Safety of Daratumumab in Relapsed/Refractory Multiple Myeloma: Data Collected from the Hungarian Hematology Centers

Background: Daratumumab is one of the most effective new myeloma drugs recently approved for relapsed/refractory multiple myeloma (MM), first in monotherapy in heavily pretreated patients, later in triplet combinations from first relapse, based on the results of the SIRIUS, POLLUX and CASTOR trials that showed good tolerability and high effectivity of daratumumab both in monotherapy and combined with lenalidomide or bortezomib. However, clinical trials are different from real world use for many reasons including less rigorous patient selection, greater flexibility with dosing and country specific funding restrictions making real world data very important for clinicians. Real world data regarding daratumumab use is currently very limited. In the Hungarian system, funding of daratumumab was initiated in December 2016, and required individual preapproved funding requests. Initially only monotherapy was reimbursed in double-refractory patients, but from 2018 triplet combination in earlier lines could start as well.Aims and Methods: The aim of this study was to evaluate the efficacy and safety of daratumumab in the real world practice. We approached all centers in Hungary where daratumumab was used, in a retrospective analysis. The scope of this study was to analyze response rate, progression free survival (PFS), treatment duration, and adverse events (AEs). Statistical analyses were performed using the SPSS (version 20.0) software package.Results: 8 centers responded with 75 patients altogether. Patients were heavily pretreated, the median number of prior lines was 3 (1-12). All patients had prior bortezomib, and most had lenalidomide (82.6%) and thalidomide (86.6%), all but one had one of the two IMiDs. 62.6% of the patients had prior autologous transplantation, with two having prior allograft, as well. Pre-daratumumab cytogenetic FISH tests of 57 patients were available, here 33/57 had high risk cytogenetics. The majority had high international staging system (ISS) score: 8, 16 and 48 were in the ISS 1, 2 and 3 groups respectively. Treatment usually continued until progression, unacceptable toxicity or death, the mean number of cycles was 6. AEs over grade 3 were uncommon, the most frequent AEs were mild infusion associated reactions (IARs, grade 1-2) and infections (Table 1). There were 7 fatal infections, other fatal AEs were absent. Infusion related toxicities were manageable in all cases. The majority of patients (41) had monotherapy with dexamethasone only, but 17 had bortezomib and another 17 lenalidomide combination. Overall response rate was assessable in 66 patients with 7 complete, 8 very good partial, 24 partial, 5 minor responses. 14 showed stable disease, 8 progressive disease. 9 patients had no formal disease reassessment due to either early death or short follow up. There was no clear connection between the number of prior lines and the quality of the response, however those who had either bortezomib or lenalidomid combinations showed better overall response rate (p=0.045).With 43 events so far the estimated PFS and OS were 151 and 260 days, but it was much better in those who showed at least a partial response (PFS 400 days, OS nor reached; Figure 1). The only other factor that significantly affected the PFS was ISS (p=0.039), we could not demonstrate a significant connection between cytogenetics, the number of prior lines, combination therapy and survival.Conclusion: Our results highlight the differences between patients treated in routine practice and those treated in clinical trials. Here treatment protocols were dictated by funding rules, and therefore similar patients were treated with doublets and triplets. The results of the POLLUX and CASTOR trials were superior in comparison to the SIRIUS study with monotherapy, but our results do not reflect this marked difference, probably due to the almost complete absence of 2nd and 3rd line patients who dominated the Pollux and Castor trials. Importantly these heavily pretreated patients tolerated daratumumab well, IARs over grade 2 were absent. Based on our results, daratumumab is an effective treatment option for relapsed/refractory MM with good safety profile. [Display omitted] DisclosuresMasszi:Janssen-Cilag: Consultancy; Takeda: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; BMS: Consultancy. Illés:Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Correlation between circulating myeloma cells and marrow myeloma cells in patients with multiple myeloma and its clinical significance

Objective To investigate the correlation between circulating myeloma cells (CMCs) and marrow myeloma cells (MMCs) in patients with multiple myeloma (MM) and assess the feasibility of CMCs reflecting the tumor load and MM progression. Methods It is a non-intervention clinical study. Between July 2015 and October 2016, 82 patients with MM from First Affiliated Hospital of Zhengzhou University were enrolled.They were divided into three groups according to the diagnosis and response criteria: newly diagnosed and relapsed group (35 cases), partial remission (PR) group (31 cases) and complete remission (CR) group (16 cases), and divided into two groups according to CMCs positive criteria: CMCs positive group (45 cases) and CMCs negative group (37 cases). Median age of the 82 MM patients(44 males, 38 females) was 58(range 33-78) years.30 patients with anemia but non-plasma cell related disorders from the same hospital in the corresponding period were screened into the control group. Median age of the 30 control subjects (18 males, 12 females) was 53(range 33-83) years.The flow cytometry was used to detect the proportions of CMCs and MMCs in each group. Other prognosis-associated factors such as hemoglobin (Hb), beta2-microglobulin (β2-MG), serumin albumin (Alb), serum creatinine (sCrea), serum calcium (Ca), lactate dehydrogenase(LDH), bone destruction, renal inadequacy, Durie-Salmon (DS) stage and international staging system (ISS) stage were simultaneously analyzed. Statistical methods including Kruskal-Wallis H test, Mann-Whitney U test, Spearman rank correlation, χ2 test and Logistic regression analysis were performed. Results (1) No CMCs and MMCs were detected in CR and control group. (2)The positive detection rates of CMCs in newly diagnosed and relapsed group and PR group were 71.4% and 64.5% respectively. The proportions of CMCs in both groups were positively correlated with those of MMCs (P<0.05). The proportions of CMCs and MMCs in newly diagnosed and relapsed group were apparently higher than those in PR group , and the proportions of CMCs and MMCs in PR group were apparently higher than those in CR group and control group (P<0.008 3). (3)The rates of moderate to severe anemia, elevated β2-MG, elevated sCrea, bone destruction and renal inadequacy in CMCs positive group were significantly increased as compared with CMCs negative group , which led to a higher DS and ISS stage (P<0.05). The multivariate logistic regression analysis indicated that moderate to severe anemia and elevated β2-MG were independent risk factors of the presence of CMCs (P<0.05). Conclusions CMCs could reflect the tumor load and the progression of disease in patients with MM.CMCs dete ction could improved the patients′ compliance as compared with MMCs. Moderate to severe anemia and elevated β2-MG were independent risk factors of the presence of CMCs in patients with MM.(Chin J Lab Med, 2017, 40: 267-272) Key words: Multiple myeloma; Neoplastic cells, circulating; Cell line, tumor; Flow cytometry

Low Pre-Transplant Vitamin D Levels Predict an Inferior Survival in Patients with Multiple Myeloma Undergoing an Autologous Stem Cell Transplant

IntroductionNearly 40% of patients with newly diagnosed multiple myeloma are vitamin D deficient (Br J Haematol. 2008;142(3):492-4). Low vitamin D levels are associated with a higher ISS (International staging system) stage, higher creatinine, and higher serum C-reactive protein levels at diagnosis (Am J Hematol. 2009;84(7):397-400). Along with its key role in bone metabolism, vitamin D promotes differentiation, inhibits proliferation and is pro-apoptotic at the cellular level. In our retrospective study, we assessed the prognostic effect of pre-transplant vitamin D levels in patients with multiple myeloma (MM) undergoing their first autologous stem cell transplant (ASCT).MethodsAll patients who underwent an ASCT for MM since 2010 were identified from the Wake Forest University Comprehensive Cancer Center registry. 25-hydroxy vitamin D levels checked within 90 prior to ASCT were recorded, along with key clinical variables as noted in table 1. Receiver operating characteristic (ROC) analysis was employed to define best discriminant levels for predicting mortality. Survival was calculated from the date of transplant to the date of death or last follow up. The JMP (SAS Institute) statistical package was used for all calculations.ResultsA total of 176 patients received ASCT for MM from 2010 to 2015, of whom 158 (90%) had pre-transplant vitamin D levels checked within 90 days of ASCT and were included in the analysis. Most patients (140/158, 89%) underwent ASCT within one year of MM diagnosis. ROC analysis identified a 25-OH vitamin D level of ≤ 23 ng/mL (AUC 0.57) as best discriminant level for predicting mortality. Using this cut-off, vitamin D deficiency was identified in 60% (94/158) patients. Low vitamin D levels were significantly associated with younger age at MM diagnosis and ASCT (P =0.001). There were no other significant differences in the baseline characteristics of patients with low versus normal vitamin D levels (Table 1). Survival from the time of transplant was inferior in vitamin D deficient patients compared to those with normal levels (HR 2.55, 95% CI 1.08-7.03; P= 0.03). Median survival in vitamin D deficient patients was 25 months versus 32 months in those with normal vitamin D levels (P= 0.03). Multivariable analysis in the context of ISS and ASBMT disease risk confirmed the independent prognostic relevance of vitamin D levels (P= 0.01).ConclusionLow pre-transplant vitamin D levels are associated with an inferior survival in patients with multiple myeloma who undergo an ASCT. Further studies are needed to determine whether repleting vitamin D in vitamin D deficient patients improves outcomes.Prognostic impact of pre-transplant vitamin D levels in MM patients undergoing an autologous stem cell transplant [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Frailty Scale Predicts Outcomes of Patients with Newly Diagnosed Multiple Myeloma Who Are Ineligible for Transplant Treated with Continuous Lenalidomide Plus Low-Dose Dexamethasone on the First Trial

Background: Many patient (pt) and disease factors have been shown to impact prognosis in multiple myeloma (MM). A recently described frailty scale categorized pts with MM into 3 groups: fit, intermediate, and frail based on age, comorbidities, and physical and cognitive functioning (Palumbo, Blood, 2015). These groups were predictive of risk of death. The pivotal phase 3 FIRST trial examined the impact of continuous therapy with lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) on outcomes in transplant-ineligible pts with newly diagnosed MM (NDMM; Benboubker, N Engl J Med, 2014). In this study, Rd continuous resulted in progression-free survival (PFS) and overall survival (OS) benefits compared with melphalan-prednisone-thalidomide (MPT). This analysis examined outcomes in pts by severity of frailty score in the FIRST trial, the largest clinical trial of transplant-ineligible NDMM to date. Methods: Pts with NDMM who were ineligible for transplant were randomized to treatment with Rd continuous, Rd for 18 cycles (Rd18; 72 weeks), or MPT for 12 cycles (72 weeks). Pts were categorized into 3 severity groups using a score based on age, Charlson Comorbidity Index score, and the Activities of Daily Living (measures of self-care) and Instrumental Activities of Daily Living (measures of usual activities) scales from the EQ-5D questionnaire at baseline, as previously described (Palumbo, Blood, 2015). This analysis examined PFS and OS outcomes by severity group in the overall pt population and between the Rd continuous and MPT arms, which were the primary comparators in this study, using an updated data cutoff of March 3, 2014. Results: This analysis included 1517 of 1623 pts from the intent-to-treat population; 106 pts were excluded because they did not have the required baseline data from the EQ-5D. The majority of pts enrolled in the FIRST trial were frail (54%) compared with fit (17%) or intermediate (30%). Similar breakdowns were observed across treatment arms (Figure 1). Frail pts were older and had higher Eastern Cooperative Oncology Group performance status scores, higher International Staging System (ISS) stage, higher lactate dehydrogenase levels, and worse renal function than fit or intermediate pts. In the overall pt population, better fitness was associated with significantly improved OS compared with worse fitness: fit vs intermediate (hazard ratio [HR] = 0.66; P = .004), fit vs frail (HR = 0.42; P Discussion: Results validated the feasibility of using the frailty scale for predicting risk of death in pts with NDMM and further demonstrated an association with PFS outcomes. The majority of pts fell into the frail category, which was associated with the poorest outcomes, indicating a need to further improve outcomes for a large proportion of pts with MM. Rd continuous resulted in PFS and OS benefits compared with MPT regardless of severity of frailty level, with the greatest benefits observed in fit pts. Poor outcomes of frail pts are likely further impacted by a higher proportion of deaths due to causes independent of MM compared with fit and intermediate pts, such as pre-existing comorbidities. These data support the use of Rd continuous as a standard frontline treatment option, even for frail pts with NDMM who are older and may have comorbidities or physical or cognitive impairments. Disclosures Facon:Celgene: Membership on an entity9s Board of Directors or advisory committees; Jansen: Membership on an entity9s Board of Directors or advisory committees; Millenium: Membership on an entity9s Board of Directors or advisory committees; Onyx: Membership on an entity9s Board of Directors or advisory committees; BMS: Membership on an entity9s Board of Directors or advisory committees. Hulin:Celgene Corporation: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Dimopoulos:Janssen-Cilag: Honoraria; Genesis: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Mohty:Celgene Corporation: Honoraria, Research Funding. Zamagni:Celgene Corporation: Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Renwick:Amgen: Other: Travel; Bayer: Speakers Bureau. Tempescul:Gilead: Other: Export Board Committee. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria. Sturniolo:Celgene Corporation: Employment. Ervin-Haynes:Celgene Corporation: Employment.

Iron Overload Pattern in Multiple Myeloma at Diagnosis its Important Clinical Associations

As a plasmaproliferative disorder, multiple myeloma (MM) is not expected to cause IO and actually there are no reports on this condition in MM. In this retrospective study, we evaluated serum iron test results in MM patients at diagnosis in order to find the frequency of IO. Iron overload pattern (IOP) was described as increased transferring saturation (> 45%) in the presence of normal to increased serum iron and ferritin levels. Among 90 newly diagnosed MM patients (54 male, 36 female, and the median age: 61 years, range: 31-86) IOP was found in 17 cases (17/90, 19%). There was a close association between lambda light chain type paraproteinemia and IOP (13/17 in IOP cohort vs 26/73 lambda paraproteinemia, p= 0.003). Half of the MM patients (7/14) with free lambda light chain paraproteinemia had IOP. The main reason of the elevated TS was increased serum iron level in IOP patients, 144 (±71) vs 57 (±24) pg/ml (p< .001). Four out of 17 IOP patients had extramedullary involvement and this was significantly more frequent than the other patients. Although high International Staging System risk disease (stage 2 or 3) was more frequent in IOP patients (15/15 vs 51/68, p= 0.03), we could not observe any difference regarding treatment response, and survival between these cases and others. In conclusion, IO is also not infrequent MM at diagnosis and it has some clinical associations.

Small compound bigelovin exerts inhibitory effects and triggers proteolysis of E2F1 in multiple myeloma cells

Multiple myeloma (MM) is a currently incurable blood cancer. Here we tested the effects of a small compound bigelovin on MM cells, and reported that it caused cell cycle arrest and subsequently induced apoptosis. Bigelovin triggered proteolysis of E2F1, which could be inhibited by caspase inhibitor. To investigate the clinical relevance, the expression of E2F1 in MM specimens was tested, and the results showed that E2F1 was overexpressed in 25-57% of MM patients and was associated with higher International Staging System (ISS) stage. These results suggest that E2F1 may be important for MM pathogenesis, and bigelovin could serve as a lead compound for the development of E2F1 inhibitor.