International Staging System Stage Research Articles

Upstaging ISS and R-ISS by Platelet Count: Real-Life Analysis of 321 MM Patients

Multiple Myeloma (MM) has to be considered a heterogeneous disease with different outcomes. International Staging System (ISS) and Revised-ISS (R-ISS) are widely and successfully used to stratify MM patients. However, it is somewhat evident a further heterogeneity across the groups defined by these scores. Risk stratification by gene mutations is an attractive method but it requires validation and it is difficult to use routinely. Some studies found platelet count prognostic for PFS and OS. Here we investigated whether a simple and reliable parameter as baseline platelet count could improve the power of ISS and R-ISS staging systems.

Abstract CT154: Melflufen in patients (pts) with relapsed/refractory multiple myeloma (RRMM) refractory to daratumumab (dara) and/or pomalidomide (pom) (OP-106)

Abstract Background: Melflufen is an alkylating peptide belonging to a novel class of peptidase-enhanced compounds. Aminopeptidases are heavily overexpressed and key for the transformation process in multiple myeloma (MM). Melflufen selectively targets MM through aminopeptidase-driven accumulation, leading to a 50-fold enrichment of alkylating metabolites vs melphalan (Chauhan et al. Clin Can Research. 2013). In the Phase I/II O-12-M1 study, melflufen showed activity in pts with RRMM (overall response rate [ORR], 31%; median progression-free survival [PFS], 5.7 mo; median overall survival, 20.7 mo), with acceptable safety (Richardson et al. Blood. 2017). The Phase II HORIZON study evaluates melflufen in pts exposed to IMiDs and proteasome inhibitors (PIs) and refractory to pom and/or dara. Methods: Pts with RRMM must have received ≥2 prior lines of therapy and have been exposed to IMiDs and PIs and refractory to pom and/or dara. Pts receive 40 mg melflufen intravenously on Day 1 of each 28-day cycle + 40 mg weekly dexamethasone. The primary endpoint is ORR (≥ partial response; investigator assessed per International Myeloma Working Group criteria). Secondary endpoints include clinical benefit rate (CBR; ≥ minimal response), PFS, and safety. Pts are treated until progressive disease (PD) or unacceptable toxicity. Results: As of 22 Oct 2018, 83 pts were treated. Median age was 63 y (35-86), median time since diagnosis was 6.5 y (0.75-25); 36% of pts were International Staging System (ISS) stage 3 and 61% had high-risk cytogenetics at study entry. Median no. of prior lines was 5 (2-13). All pts were pom or dara refractory, 60% were pom and dara refractory and 86% were double refractory (IMiD and PI). Also, 84% had received prior alkylator therapy (55% alkylator refractory); 69% had received ≥1 prior transplant. Treatment was ongoing for 23% of pts and discontinued in 77% of pts due to PD (57%), adverse event (AE; 13%), or other (7%). Treatment-related grade 3/4 AEs were reported in 62 (75%) pts, mostly hematologic: neutropenia (61%), thrombocytopenia (59%), and anemia (25%). Treatment-related non-hematologic grade 3/4 AEs were rare (eg, infections in 7% of pts). Fourteen (16%) pts experienced treatment-related serious AEs, most commonly febrile neutropenia (n=5), neutropenia (n=3), and thrombocytopenia (n=2). No treatment-related deaths were reported. In total, 82 pts were evaluable for response: ORR was 33% and CBR 39%. Benefit was observed for high-risk subgroups: ORR for pts with ISS stage 3, high-risk cytogenetics, and double- and dara-refractory disease was 24%, 22%, and 19%, respectively. Median PFS was 4.0 mo (95% CI, 3.3-5.1). Conclusion: Melflufen has promising activity in heavily pretreated, multi-refractory late-stage pts with RRMM. Melflufen was generally well tolerated with infrequent non-hematologic AEs and low rates of discontinuation due to AEs. Citation Format: Paul G. Richardson, Albert Oriol, Alessandra Larocca, Paula Rodriguez Otero, Jan Moreb, Joan Bladé, Hani Hassoun, Michele Cavo, Adrián Alegre, Amitabha Mazumder, Christopher Maisel, Agne Paner, Xavier Leleu, Jeffrey A. Zonder, Johan Harmenberg, Sara Thuresson, Hanan Zubair, María-Victoria Mateos. Melflufen in patients (pts) with relapsed/refractory multiple myeloma (RRMM) refractory to daratumumab (dara) and/or pomalidomide (pom) (OP-106) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT154.

PF732 AN INDEPENDENT OBSERVATIONAL STUDY OF REAL LIFE COSTS OF CARE TO MYELOMA PATIENTS IN THE ERA OF NOVEL THERAPIES

Background:Novel haematological therapies offer advantages in management of malignant and non‐malignant conditions, but treatment access is limited by cost, typically referenced as medication cost alone. The addition of real world costs of care provides a more complete cost‐benefit analysis, and limited published data and common perception have suggested additional costs are greater for novel agents.Aims:We analysed and compared total dollar value costs of care excluding the cost of the novel agent for myeloma patients treated first‐line with bortezomib and non‐novel agent based regimens in an inclusive (encompassing all patients within a local health network), real‐world cohort.Methods:We interrogated electronic and case note databases to record hospital admissions, outpatient visits, investigations, and non‐primary‐therapy medications and costed these using standard values using single payer government benchmarks. The primary end point was the real world cost of treatment per patient for the first year of treatment.Results:After using generalised linear models to adjust for patient age, gender, International Staging System (ISS) stage, trial status and transplant status, the mean yearly cost of care for patients receiving bortezomib‐based regimens was AU$24,162 (CI $20,207–28,118), which was 2.6% lower (CI −22.1–21.7, p = 0.814) than that for those receiving regimens not containing a novel agent ($26,300, CI $23,121–29,479) excluding the novel agent. Compared to patients at Stage 1 at baseline ($, CI$‐), costs of care were 62.2% higher (CI 50.1–81.8, p < .0001) for patients at Stage 3 at baseline ($, CI$‐). Costs were 36.0% lower (CI 18.2–49.9, p < .0001) for trial patients ($21,381, CI $17,404–25,358) compared to non‐trial patients ($25,130, CI $20,120–30,139). Yearly costs of care are estimated to be on average 51.5% higher (CI 22.0–88.1, p < .0001) for transplant patients ($27,288, CI $23,351–31,226) compared to non‐transplant patients ($17,088, CI $10,980–23,196).Summary/Conclusion:Contrary to common perceptions and previously published data, bortezomib‐based regimens do not confer higher costs of care in the real world than conventional regimens. Subgroup analysis indicates significant cost differences based on ISS stage, trial involvement, transplant status and age.

Expressions of CD117 and CD28 in patients with newly diagnosed multiple myeloma and their clinical significances

Objective To investigate the expressions of CD28 and CD117 in patients with newly diagnosed multiple myeloma (MM) and their clinical significances. Methods The clinical data of 115 newly diagnosed MM patients in the First Affiliated Hospital of Zhengzhou University from May 2015 to December 2017 were retrospectively analyzed. The expressions of CD28 and CD117 were detected by using multiparameter flow cytometry. The relationship between the expressions of CD28 and CD117 and MM staging and clinical parameters was analyzed. The staging was performed according to the International Staging System (ISS). Results Among these 115 patients, there were 15 patients with CD117 positive and 30 patients with CD28 positive. Erythrocyte sedimentation rate (r = -0.481, P = 0.039), C-reactive protein level (r = -0.314, P = 0.015), the proportion of plasma cells detected by bone marrow cytology (r = -0.027, P = 0.001) were negatively correlated with CD117 positive expressions. CD28 positive expression was positively correlated with lactate dehydrogenase level (r = 0.249, P = 0.033) and ISS stage (r = 0.319, P = 0.017), while it was negatively correlated with hemoglobin level (r = -0.372, P = 0.026). CD28 positive was associated with light chain type, and non-secretory type mostly occurred (P = 0.016). The incidence of osteolytic lesions in CD28 positive group and CD117 positive group was high, but there was no statistical difference between CD28 positive group, CD117 positive group and CD28 negative group, CD117 negative group (P = 0.052, P = 0.479). Conclusions The positive expression of CD117 in the early stage of MM patients is higher than that in the advanced stage, and the expression of CD28 positive in the advanced stage of MM patients is higher than that in the early stage. CD28 and CD117 can be used as indicators of prognosis stratification in the patients with newly diagnosed MM. Key words: Multiple myeloma; Antigens, CD28; Antigens, CD117; Flow cytometry

Retrospective analysis of the efficacy and influencing factors of autologous hematopoietic stem cell transplantation for multiple myeloma.

This study aims to review the clinical efficacy and factors affecting the treatment of multiple myeloma (MM) by autologous hematopoietic stem cell transplantation (ASCT). The clinical data of 47 patients with MM from the Department of Hematology of Henan Cancer Hospital from September 2010 to July 2018 were retrospectively analyzed. At pre-transplantation of autologous cells, 25.5% were in complete remission (CR), 14.9% were in very good partial remission (VGPR) and 59.6% were in partial remission (PR). Among these cases, one case had PR after three recurrences. At post-transplantation, 51% were in CR, including two cases who received double transplantations, 27.7% were in VGPR, and 21.3% were in PR. The median follow-up time was 27.6 months (4-96 months). The 3-year progression free survival (PFS) and overall survival (OS) were 47.9% and 79.6%, respectively. The Analysis of variance (ANOVA) results revealed that factors that affected OS were international staging system (ISS) stage (P=0.002), CR and VGPR post-transplantation (P=0.002), while factors that affected PFS were ISS stage (P=0.005), pre-transplant induction therapy (P=0.032), and disease risk stratification (P=0.017). The curative effects for PFS were CR and VGPR pre-transplantation (P=0.013) and post-transplantation (P=0.011). The Cox multivariate regression analysis revealed that ISS stage and CR and VGPR post-transplantation were independent prognostic factors of OS. At post-transplantation, CR and VGPR, ISS stage, and pre-transplant induction therapy were independent prognostic factors for PFS. In conclusion, ASCT can improve the clinical efficacy and survival rate of MM patients. ISS stage, CR and VGPR post-transplantation are independent prognostic factors of OS and PFS, while pre-transplant induction therapy is an independent prognostic factor for PFS.

Survival rate of multiple myeloma patients in Indonesia: A retrospective study in multiple myeloma at a single institution.

IntroductionTo evaluate the response and the correlation between survival and prognostic factors in 32 patients with multiple myeloma.MethodWe recruited 32 patients (18 men and 14 women) with mean age 59 years old who were diagnosed with multiple myeloma that were treated with surgery (n = 21) and without surgery (n = 11). 9 patients underwent hemiarthroplasty, 14 patients underwent open reduction and internal fixation and 4 patients underwent spinal decompression and posterior pedicular instrumentation from January 2012 to December 2017. In this group, there were 6 patients who underwent more than one surgeries. Patients were classified using the International Staging System (ISS) for multiple myeloma by evaluated albumin and β2-microglobulin level.ResultsThe mean follow up period for 32 patients was 30.2 months (range, 3–65 months) with 7 patients in ISS stage I, 22 patients in ISS stage II and 3 patients in ISS stage III. The median survival duration was 28 months (95% CI). We documented the median survival for ISS stage II disease was 29 months, stage III disease 6 months and stage I disease 16 months with the median age of ISS stage I, II, and III disease was 65, 59, 60 years respectively. Survival correlation with ISS stage (p = 0.009), the hemoglobin level (p = 0.772), and the calcium level (p = 0.926).ConclusionsThe survival rate was lower in patients with higher ISS stage for this disease. Survival rate seems to be better among younger patients than in older ones even with lower ISS stage of this disease.

Outcomes with early response to first-line treatment in patients with newly diagnosed multiple myeloma

AbstractWe evaluated the impact of achieving a rapid response in 840 newly diagnosed multiple myeloma patients from 2004 to 2015. Rates of very good partial response (VGPR) or better were 29% (240/840) after 2 cycles of treatment, 42% (350/840) after 4 cycles of treatment, and 66% (552/840) as best response. Early responders after 2 cycles of treatment had higher rates of light chain disease, anemia, renal failure, International Staging System (ISS) stage III disease, and high-risk cytogenetics, especially t(4;14), and were more likely to have received triplet therapy and undergo transplant. Median progression-free survival (PFS) and overall survival (OS) were not different among patients with ≥VGPR and <VGPR after 2 cycles (PFS, 28 vs 30 months, P = .6; OS, 78 vs 96 months, P = .1) and 4 cycles (PFS, 31 vs 29 months; OS, 89 vs 91 months, P = .9), although both were improved, with ≥VGPR as best response (PFS, 33 vs 22 months, P < .001; OS, 102 vs 77 months, P = .003). On multivariate analysis stratified by transplant status, achievement of ≥VGPR after 2 cycles was not associated with improved PFS (hazard ratio [95% confidence interval]; transplant cohort, 1.1 [0.7-1.6]; nontransplant cohort, 1.2 [0.8-1.7]) or OS (transplant cohort, 1.6 [0.9-2.9]; nontransplant cohort, 1.5 [1.0-2.4]). Covariates in the model included high-risk cytogenetics, ISS stage III, triplet therapy, creatinine ≥2 mg/dL, light chain disease, and age. Although patients with high-risk disease are more likely to achieve early response, a rapid achievement of a deep response by itself does not affect long-term outcomes.

Substratification of patients with newly diagnosed standard-risk multiple myeloma.

Despite the absence of high-risk cytogenetics and lower International Staging System (ISS) stages, a subset of patients with multiple myeloma (MM) experience poor overall survival (OS). We studied 1461 patients with newly diagnosed MM to identify patient and disease characteristics that predict a high-risk phenotype among standard-risk patients. Fifty-six percent of all patients presented with standard-risk disease. Among them, advanced age, extremes of body mass index, non-hyperdiploid karyotype and abnormal lymphocyte counts were associated with worse OS. Standard-risk patients with 0-1 of these adverse factors (hazard ratio [HR] 0·32, 95% confidence interval [CI] 0·24-0·43, P<0·001) and 2 adverse factors (HR 0·54, 95% CI 0·41-0·72, P<0·001) experienced better OS than high-risk patients. Two or more adverse factors were present in 17% of standard-risk patients and were associated with OS comparable to high-risk patients (HR 0·91, 95% CI 0·67-1·24, P=0·548). Predictive power among standard-risk patients was improved using score groups compared to ISS stages. Patients with standard-risk MM are a heterogeneous group with one in six patients experiencing OS comparable to high-risk disease. Patients at risk can be identified using readily available patient and disease characteristics. These findings emphasize the importance of accurate risk stratification and help explain part of the heterogeneity observed in clinical practice.

PKP/PVP combine chemotherapy in the treatment of multiple myeloma patients with vertebral pathological fractures: minimum 3-year follow-up of 108 cases

BackgroundMultiple myeloma (MM) is a blood system malignant tumor, which often leads to osteolytic bone destruction, and the vertebral column is the primary site of involvement. However, the efficacy and prognosis of percutaneous kyphoplasty/vertebroplasty (PKP/PVP) for simple vertebral pathological fractures in patients with multiple myeloma are not yet unified. The primary objective of this study was to investigate the efficacy and prognosis of PKP/PVP in the treatment of multiple myeloma patients with vertebral pathological fractures.MethodsA total of 108 patients with MM from Beijing Chao-Yang Hospital from 2007 to 2013 were enrolled. Of these, 52 patients underwent PKP/PVP surgery and chemotherapy (surgery group) and 56 received only chemotherapy (chemotherapy group). The age, gender, International Staging System (ISS), fracture location, segment, visual analog scale (VAS), Oswestry Disability Index (ODI), comprehensive treatment satisfaction, stem cell transplantation, overall survival (OS), mortality rate, and the cause of death of patients were recorded; the mean follow-up time was 42.46 months.ResultsThe average age of patients in surgery and chemotherapy groups was 60.8 years and 58.1 years, and the mean survival time was 41.98 months and 43.30 months, respectively. The VAS score at 1 month and last follow-up after treatment in surgery group were significantly lower than those in the chemotherapy group (P < 0.05); the ODI at 1 month after treatment in the surgery group was significantly lower than that in the chemotherapy group (P < 0.05); no significant difference was observed in the 3-year mortality rate between surgery and chemotherapy groups. The number of patients who developed activity disorder in the surgery group was significantly less than that in the chemotherapy group (P < 0.05). The OS of patients in ISS stage III was significantly less than that in ISS stages I and II (P < 0.05).ConclusionsPKP/PVP surgery can greatly relieve the pain caused by fractures, reduce the risk of being completely bedridden and pulmonary infection, and improve the quality of life of patients; however, it did not affect mortality rate and overall survival time in patients.Trial registrationAs this was a retrospective study, it did not require ethical approval; all patients had signed informed consent when they received treatment, and all treatment options were voluntary.

Development and Validation of a 9-Gene Prognostic Signature in Patients With Multiple Myeloma.

Background: Multiple myeloma (MM) is one of the most common types of hematological malignance, and the prognosis of MM patients remains poor.Objective: To identify and validate a genetic prognostic signature in patients with MM.Methods: Co-expression network was constructed to identify hub genes related with International Staging System (ISS) stage of MM. Functional analysis of hub genes was conducted. Univariate Cox proportional hazard regression analysis was conducted to identify genes correlated with the overall survival (OS) of MM patients. Least absolute shrinkage and selection operator (LASSO) penalized Cox proportional hazards regression model was used to minimize overfitting and construct a prognostic signature. The prognostic value of the signature was validated in the test set and an independent validation cohort.Results: A total of 758 hub genes correlated with ISS stage of MM patients were identified, and these hub genes were mainly enriched in several GO terms and KEGG pathways involved in cell proliferation and immune response. Nine hub genes (HLA-DPB1, TOP2A, FABP5, CYP1B1, IGHM, FANCI, LYZ, HMGN5, and BEND6) with non-zero coefficients in the LASSO Cox regression model were used to build a 9-gene prognostic signature. Relapsed MM and ISS stage III MM was associated with high risk score calculated based on the signature. Patients in the 9-gene signature low risk group was significantly associated with better clinical outcome than those in the 9-gene signature high risk group in the training set, test, and validation set.Conclusions: We developed a 9-gene prognostic signature that might be an independent prognostic factor in patients with MM.

High-dose chemotherapy followed by autologous stem cell transplant for multiple myeloma: Predictors of long-term outcome.

Background & objectives:Survival of patients with multiple myeloma (MM) has improved in the past two decades following use of novel agents and autologous stem cell transplantation. To determine predictors of long-term outcome, data of MM patients who underwent autologous stem cell transplantation (ASCT) at a tertiary care centre in north India were retrospectively analyzed.Methods:Between 1995 and 2016, 349 MM patients underwent ASCT. Patients' median age was 52 yr, ranging from 29 to 68 yr, 68.2 per cent were males. Thirty three per cent patients had international staging system (ISS) Stage III and 68.5 per cent had received novel agents-based induction. High-dose melphalan (200 mg/m2) was used for conditioning; patients with renal insufficiency (estimated glomerular filtration rate <40 ml/min) received melphalan 140-150 mg/m2.Results:Post-transplant, 317 of 349 (90.8%) patients responded; complete [complete response (CR)] −213 (61%)], very good partial response (VGPR) −62 (17.8%) and PR in 42 (12%)]. Induction with novel agents, pre-transplant chemosensitive disease, transplant in first remission and serum albumin (≥3.5 g/dl) were predictors of significant response. At a median follow up of 73 months, median overall survival (OS) was 90 months [95% confidence interval (CI) 70.8-109.2], and progression-free survival (PFS) was 41 months (95% CI 33.0-49.0). On multivariate analysis, achievement of CR post-transplant, transplant in first remission, ISS Stages I and II (vs. III), absence of extramedullary disease and serum albumin ≥3.5 g/dl were predictors of prolonged OS. For PFS, achievement of post-transplant CR and transplant in first remission were predictors of superior outcome.Interpretation & conclusions:Treatment with novel agents, achievement of complete remission post-transplant, ISS Stages I and II, absence of extramedullary disease and transplant in first remission were predictors of long-term survival for patients with MM.

Assessment of Red Blood Cell Distribution Width and Multiple Myeloma in a Guangxi Population: a Retrospective Study.

Red blood cell distribution width (RDW) has been reported as a marker for inflammation and tumors. The present study aims to investigate the use of RDW in patients with multiple myeloma (MM). Seventy-three patients with newly diagnosed symptomatic multiple myeloma (SMM), 39 patients with relapsed multiple myeloma (RMM), and 91 healthy individuals were recruited into this study. The demographic and laboratory parameters were reviewed retrospectively, and the correlation between RDW and other parameters among groups were evaluated by Spearman's correlation analysis. The sensitivity and specificity of RDW were determined by receiver operating characteristic (ROC) curve analysis. The RDW values in both SMM and RMM were significantly higher than in the healthy individuals (p < 0.001). In SMM patients with International Staging System (ISS) Stages II and III, the level of RDW was higher than in the patients with ISS Stage I; however, there was no significant difference between each ISS stage in RMM patients. The RDW strongly correlated with platelet distribution width (PDW), cystatin C, serum beta2-microglobulin (Sβ2M), hemoglobin (HGB), hematocrit (HCT), albumin (Alb), and calcium (p < 0.05) in SMM patients, and RDW in RMM patients had a positive or negative correlation with PDW, Sβ2M, globulin, HGB, absolute neutrophil count, platelet count, HCT, and Alb (p < 0.05). The ROC curve analysis showed that RDW > 13.5 had 94.5% sensitivity and 63.7% specificity for SMM, and 92.3% sensitivity and 63.7% specificity for RMM. Elevated RDW in MM patients was associated with the stage of the disease.

Identification of High Serum Apolipoprotein A1 as a Favorable Prognostic Indicator in Patients with Multiple Myeloma.

This study is to explore the prognostic significance of serum lipid profiles in patients with multiple myeloma (MM). The study retrospectively enrolled 307 MM patients in Zhongshan Hospital, Shanghai, China, from 2007 to 2016. We evaluated the prognostic significance of the pre-diagnostic serum lipid profile [cholesterol, triglyceride, low-density lipoprotein (LDL), high-density lipoprotein (HDL), Apolipoprotein A1 (Apo A1) and Apolipoprotein B (Apo B)]. Prognostic factors identified through univariate and multivariate analysis were used to construct a new model based on Lasso Cox regression. Results indicated that lipid levels showed significant difference between ISS stages: Apo A1, Apo B, Cholesterol and LDL levels were lower in late ISS stage. However, only Apo A1 showed statistically significance in overall survival (OS), progression free survival (PFS) and cause specific survival (CSS) (P=0.038, P=0.028, P=0.011) in univariate Cox regression. Patients with higher Apo A1 displayed longer OS (median OS, 67 months vs. 30 months; P<0.001). Also, Apo A1 was revealed to be an independent prognostic indicator through multivariate analysis. Combining the Apo A1 level, Zhongshan Score model was constructed with Lasso regression for prognosis prediction. This model exhibited higher accuracy than International Staging System (ISS) and Durie and Salmon (DS) system. In conclusion, among all the serum lipid profiles, serum Apo A1 is a powerful prognostic indicator for patients with MM.

Combination of Genetic Aberration With International Staging System Classification for Stratification of Asian Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation.

The aim of the study was to contribute to the development of adaptive risk stratification methods specific to Asian multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT). We conducted this study to evaluate the prognostic impact of genetic abnormalities detected by fluorescent in situ hybridization (FISH) on survival outcomes in combination with the International Staging System (ISS) classification in 161 MM patients. This was a single-center retrospective longitudinal cohort study of newly diagnosed MM patients undergoing ASCT within 12 months from initial diagnosis. A single-center retrospective cohort study of newly diagnosed MM. Patients were divided into 3 groups according to risk stratification: 1) low-risk, patients without del(17p13) nor t(14;16) or t(4;14) and ISS I/II; 2) high-risk, patients with t(4;14), regardless of ISS stage; 3) intermediate-risk, all remaining patients. The median PFS for the low-risk group was 18 months versus 13 months for the intermediate group (p=0.047, HR=1.527, 95%CI=1.006-2.316) versus 10 months for the high-risk group (p<0.001, HR=2.656, 95%CI=1.572-4.490). An ISS/FISH-based prognostication strategy was developed that can predict PFS for Asian MM patients undergoing ASCT.

Dynamic Changes in International Staging System As a Predictor of Survival Outcome in Patients with Advanced Multiple Myeloma

Background: The International Staging System (ISS) based on serum beta-2 microglobulin and serum albumin is a useful tool for risk stratification in patients with multiple myeloma. ISS is usually assessed at the time of diagnosis. Recent studies have suggested that risk stratification should be considered dynamic over the disease course. Our study aimed to describe dynamic changes in ISS over time and their impacts on mortality in patients with advanced multiple myeloma.Methods: This study included 417 patients with multiple myeloma from the Flatiron medical records database (Jan 2011- May 2018) who have received at least two lines of therapy and had data on ISS at the time of diagnosis (TDX) and at the time of initiating the second line of therapy (T2L). ISS stage was either abstracted from medical records or derived from the results of laboratory tests of serum beta-2 microglobulin and serum albumin. Patients were followed up from T2L until the earliest event of the last activity in database or death. We calculated mortality rates by TDX and T2L ISS stages, and generated Cox proportional hazard models to estimate the impact of TDX and T2L ISS stages on mortality. Additionally, in the subgroup of patients in ISS stage III at TDX, we used univariate logistic models to identify the predictors for downward shift to ISS stage I or II at T2L.Results: The study cohort had a median age of 70 (interquartile range: 61 to 77), and 59% were male. Based on ISS at TDX, 30%, 37%, and 33% of the study cohort were classified as stage I, II, and III with the mortality rate of 12, 11, and 24 deaths per 100 person-years, respectively. The hazard ratios were 0.95 (95% confidence interval (CI): 0.57-1.61) for patients in stage II and 1.96 (95% CI: 1.22-3.16) for patients in stage III, compared with patients in stage I. Based on ISS at T2L, 47%, 34%, and 20% were classified as stage I, II, and III, with the mortality rate of 7, 19, and 39 deaths per 100 person-years, respectively. The hazard ratios were 2.62 (95% CI: 1.61-4.25) for patients in stage II and 5.18 (95% CI: 3.10-8.64) for patients in stage III, compared with patients in stage I.Dynamic changes in ISS stages over time and mortality rates were depicted in the Table. Among patients in ISS stage I at TDX, about 25% shifted to higher stages at T2L, and had a higher mortality rate (26 per 100 person-years) than did patients remaining in stage I (8 per 100 person-years). For patients in ISS stage II at TDX, 43% stayed in Stage II at T2L, and 46% moved down to Stage I, with a mortality rate of 20 and 5 per 100 person-years, respectively. Among patients in ISS stage III at TDX, 58% moved down to lower stages at T2L. The mortality rate was 10, 21, and 40 per 100 person-years for patients moving down to Stage I and II at T2L and those remaining in Stage III, respectively. In the subgroup of patients in ISS stage III at TDX, strong predictors for shifting down to lower stages were younger age (odds ratio: 2.65; 95% CI:1.20-5.87 for age <65 vs ≥65 years) and serum creatinine ≤ 2 mg/dL at TDX (odds ratio: 2.26; 95% CI:1.03-4.92 for serum creatinine ≤ 2 vs >2 mg/dL), but not gender, race, or cytogenetic abnormality of del17p, t(4;14), and t(14;16).Conclusion: Large changes in ISS stages were observed in multiple myeloma patients when advancing the line of therapy. Changes in ISS stage were also associated with survival outcome. A downward shift to stage I was associated with substantially improved overall survival; in contrast, patients moving up to or remaining in higher stages had poor outcomes, especially for those remaining in ISS stage III. Our results suggest that re-evaluating ISS stage at the time of change in line of therapy can improve prediction of survival outcomes. [Display omitted] DisclosuresHong:Takeda Pharmaceuticals International Co.: Employment. Crossland:Takeda Pharmaceuticals International Co.: Employment. Galaznik:Takeda Pharmaceuticals International Co.: Employment. Dolin:Shire: Other: PD holds shares in Shire ; GSK: Other: PD holds shares in GSK; Takeda Pharmaceuticals International Co.: Employment.

Development of Thrombocytopenia and Survival Outcomes in Newly Diagnosed Multiple Myeloma

Introduction: Thrombocytopenia is a major dose-limiting hematologic toxicity of anti-myeloma therapy. Clinical trial data in the relapsed/refractory setting have linked the development of thrombocytopenia during therapy with bortezomib with improved response to treatment. Less is known about the prognostic significance of early treatment related thrombocytopenia during initial therapy for newly diagnosed multiple myeloma (MM) using novel agents.Aims: The aim of this study was to characterize the effect of new, treatment related thrombocytopenia during initial therapy for newly diagnosed MM with novel agents on survival and clinical response.Methods: We identified 690 patients with newly diagnosed MM treated at Mayo Clinic, Rochester from January 2004 to December 2015 through a retrospective record review. All patients received novel agents including proteasome inhibitors (PI) and/or immunomodulatory drugs, were evaluable using the International Myeloma Working Group uniform response criteria, and had platelet counts greater than 150,000/µL prior to initial treatment. Survival outcomes and response were compared in patients who became thrombocytopenic within two cycles of first line treatment, defined as a nadir platelet count less than 150,000/µL, and in patients who did not develop thrombocytopenia. Survival estimates were calculated using the Kaplan-Meier method, and the log-rank test was used to compare survival in subgroups. Multivariable-adjusted proportional hazards regression models were fit to adjust for known prognostic factors including age, sex, International Staging System (ISS) stage, and the presence of cytogenetic high-risk abnormalities. Logistic regression was performed to evaluate for differences in response between groups. P-values less than 0.05 were considered statistically significant.Results: Of the 690 patients treated with novel agents, 495 patients (72%) received a PI as initial therapy. Median follow up was 3 years (0.1-13.2), median overall survival (OS) was 6.6 years (95% CI 5.9-8.0), and median progression free survival (PFS) was 4.84 years (95% CI 3.53-8.98). 123 patients (18%) developed thrombocytopenia within two cycles of first line therapy; two patients developed platelet counts less than 20,000/µL and none developed counts less than 10,000/µL. Differences in survival estimates for OS and PFS for patients who did not develop thrombocytopenia and those who became thrombocytopenic are illustrated in Figure 1. Median OS in patients who did not develop thrombocytopenia was 7.4 years (95% CI 5.9-8.9), compared to 4.6 years (95% CI 4.1-6.0) in those who became thrombocytopenic (p = 0.003), while median PFS was 5.4 years (95% CI 3.63-NR) and 3.53 years (95% CI 0.49-NR), respectively (p = 0.008). Similar results for both OS and PFS were observed when using a platelet nadir of less than 100,000/µL. These relationships remained statistically significant when adjusting for the effect of known prognostic factors including age, sex, ISS stage, and high-risk cytogenetics, for both OS and PFS (HR = 1.70, 95% CI 1.12-1.59, p = 0.013, n = 387 and HR = 1.56, 95% CI 1.03-2.37, p = 0.036, n = 387, respectively). Multivariable-adjusted estimates were similar for the subset of patients receiving PI containing regimens. Development of thrombocytopenia within two cycles was not associated with very good partial response or better (VGPR+) (p = 0.588) or with complete response (CR) (p = 0.968). This was also true for the subset of patients receiving PIs (p = 0.827 and p = 0.772, respectively).Conclusions: Our results suggest that the development of new, treatment related thrombocytopenia within two cycles of first-line therapy with novel agents is independently associated with inferior survival in newly diagnosed MM. This was also true in the subset of patients receiving PI containing regimens. In contrast to prior studies, there was no association between early treatment-related thrombocytopenia and response to treatment for either novel agents in general or PI based therapies.Figure 1: Kaplan-Meier progression free and overall survival estimates stratified by platelet count ≥ 150,000/µL (no thrombocytopenia) and <150,000/µL (new thrombocytopenia) within two cycles of initial therapy with novel agents. [Display omitted] DisclosuresLacy:Celgene: Research Funding. Gertz:Prothena: Honoraria; Teva: Consultancy; Ionis: Honoraria; Alnylam: Honoraria; Research to Practice: Consultancy; Apellis: Consultancy; Physicians Education Resource: Consultancy; janssen: Consultancy; spectrum: Consultancy, Honoraria; Amgen: Consultancy; Abbvie: Consultancy; Medscape: Consultancy; annexon: Consultancy; celgene: Consultancy. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Clinical Features and Predictive Factors of Early Mortality in Patients with MM Outside of Clinical Trials

BackgroundNovel agents such as proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) have improved the overall survival of patients with newly diagnosed multiple myeloma (NDMM) over the last decade. However, early mortality (EM) remains a serious obstacle for a portion of the patients despite receiving novel agents. The report based on clinical trials showed that age, International Staging System (ISS), lactate dehydrogenase (LDH) levels, and high-risk cytogenetic abnormalities (CA) predict EM due to myeloma progression. The result, however, may differ from real-world settings because the patients of clinical trials are relatively younger and have fewer health problems, and the major cause of EM is not only disease progression, but also infections and comorbidities. In this study, we retrospectively analyzed the clinical variables that affected EM in patients with multiple myeloma (MM) in the real-world setting in the novel agent era.Patients and MethodsThe study population consisted of 238 consecutive patients with NDMM between January 2008 and April 2018 at Kameda Medical Center, Japan. All patients were administered PI- or IMiD-based combined chemotherapy in the frontline setting. Patients diagnosed with smoldering MM and solitary plasmacytoma and who did not receive treatment were excluded in this study. Early mortality was defined as death within two years after diagnosis due to any cause. Comorbidities were evaluated according to the Charlson Comorbidity Index (CCI). Instrumental Activities of Daily Living (IADLs) were retrospectively scored based on medical records. IADLs were assessed by the percentage of the score because the full score of IADLs is different between men and women. High-risk CA was defined by the presence of t(4;14), t(14;16), and del(17p). Statistical analyses were performed with EZR, which is a graphical user interface for R ver. 3.2.2.Ethical considerationsThis study was approved by the institutional review board of Kameda Medical Center and conducted according to the principles of the Declaration of Helsinki.ResultsThe median age of the patients was 72.2 years, and the median observation period was 40.8 months. Fifty patients (21.3%) died within two years. The major causes of mortality were myeloma progression (36%), infection (22%), and comorbidities (20%). Baseline involved free light chain (iFLC), LDH > normal range, and high-risk CA were not statistically significant between the patients with or without EM. There were significant differences in age, reduction in iFLC on day 7 from the baseline, ISS stage, Revised-ISS stage, Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≥3, CCI score ≥4, and the percentage of IADL scores between the two groups (Table1). Next, we analyzed IADL scores and the reduction in iFLC on day 7 because these variables were not assessed in previous studies. Receiver-operating characteristic curve analysis showed that the best cutoff values were 50% for IADL scores and 65% for the reduction in iFLC on day 7. Univariate analysis suggested that the factors associated with EM were age >75 years, ISS stage 3, CCI score ≥4, ECOG-PS ≥3, IADL <50%, and iFLC reduction >65% on day 7. The multivariate analysis showed that CCI score ≥4 [odds ratio (OR), 2.43; 95% confidence interval (CI), 1.11-5.32; p=0.027], IADL score <50% (OR, 3.31; 95% CI, 1.42-7.70; p=0.006), and iFLC reduction >65% on day 7 (OR, 3.20; 95% CI, 1.45-7.07, p=0.004) were independent predictive factors for EM (Table2). Thus, the EM predictive score was established according to following variables: CCI score ≥4, IADL score <50%, iFLC reduction >65% on day 7, and ISS stage 3. Sixty patients were categorized with high scores (score ≥3), and half of the patients with high scores died within two years, while only 10% of the patients with low scores (score <3) died within two years (p<0.001).ConclusionOne-fifth of the patients with NDMM died within two years due to myeloma progression, infection, and comorbidities. Our results suggested that high-risk CA and high levels of LDH did not have predictive value for EM in patients with NDMM outside of clinical trials. The presence of high CCI scores, low IADL scores, and decreases in iFLC (>65%) on day 7 from the baseline were independent prognostic factors, which could reflect both patient and disease factors. The combination of the CCI score, IADL score, ISS stage, and early reduction in iFLC may help in the identification of EM. DisclosuresNo relevant conflicts of interest to declare.

Differential Effect of Upfront Intensification Treatment in Genetically Defined Myeloma Risk Groups - a Combined Analysis of ISS, Del17p and SKY92 Scores in the EMN-02/HOVON-95 MM Trial

Differential Effect of Upfront Intensification Treatment in Genetically Defined Myeloma Risk Groups - a Combined Analysis of ISS, Del17p and SKY92 Scores in the EMN-02/HOVON-95 MM Trial

Predictors of Overall Survival for Multiple Myeloma Patients Depending on Transplant Status According to a Retrospective, Non-Interventional Study in Norway

IntroductionMultiple myeloma (MM) is the second most common hematological malignancy in Europe and the US. The median survival after diagnosis is approximately 4-5 years (Röllig et al The Lancet 2015), with recent improvement observed in younger (Kyle et al Expert Rev Hematol 2014) and older patients (Kumar et al Leukemia 2013). The improvement in outcomes of MM patients is largely due to the introduction of autologous stem cell transplant (ASCT) and novel treatments including proteasome inhibitors and immunomodulators. Norwegian guidelines state that the preferred frontline treatment for MM patients under 65-70 years old is ASCT, but this option may be limited by comorbidity. Here, we report results from a retrospective, non-interventional study using data collected at the MM registry at Oslo University Hospital (OUS), Norway. The aim was to describe patient and disease characteristics, overall survival (OS), and potential predictors of death for the study population in Norway.MethodsThe study period was from 1 Jan 2008 to 31 Dec 2015. Patients (n=169) aged 18 years or older at MM diagnosis and who were treated at OUS (ASCT or not) or in 1 of 5 regional hospitals (ASCT only, with ASCT received at OUS and other treatments received locally), during the study period, were included. Study entry was defined as date of MM diagnosis and follow-up started from study entry. End of follow-up occurred at the first of: end of study period, loss to follow-up, or death. Variables used were part of routine practice. Descriptive analysis was done at diagnosis for the overall population, for patients who received ASCT (n=100), and for those who did not receive ASCT at any time during the study period (n=69). At treatment line 1, Cox models were used to identify potential predictors for OS.ResultsIn the study, 55.6% of patients were diagnosed with MM at OUS and 25 of those patients (14.8% of total population) received ASCT. Patients who did not receive ASCT were older and included a larger percentage of women than in the transplant cohort (mean age non-ASCT 73.1±11.2 with 55.1% women and for ASCT 55.5±6.7 years with 45.0% women).More MM patients were diagnosed with Bence Jones (BJ) (21.9% of patients) or IgG type myeloma (54.4% of patients) than IgA type (20.1% of patients) (Table 1). Of transplant patients, more were of International Staging System (ISS) stage I or stage II than stage III MM, though 35.0% of patients were of unknown stage. Most non-transplant patients had unknown ISS stage, followed by stages II and III and the least number of patients were of stage I.Of the CRAB symptoms at diagnosis, most ASCT patients showed no hypercalcemia (80.0%), no renal impairment (90.0%), or no anemia (68.0%), and 34.0% presented with skeletal destruction (Table 1). Similarly, most non-transplant patients had no hypercalcemia (87.0%) and no renal impairment (79.7%) at diagnosis. Anemia and skeletal destruction were not measured in 24.6% of non-transplant patients. Of those with recorded results, more non-transplant patients had skeletal destruction than not and approximately the same number of non-transplant patients presented with anemia than not. High-risk cytogenic abnormalities, a criterion of the revised (R)-ISS, was unknown for most patients (80.5%).Median OS from start of treatment line 1 was 75.93 (90% confidence interval (CI): 68.23 to not reached) months for transplant patients and 34.20 (90% CI: 25.57-42.16) months for non-transplant patients. Variables including age group, sex, CRAB symptoms at diagnosis, type of first therapy, and type of MM at diagnosis were included in the Cox models per cohort, if they had a missingness of <20%. Hypercalcemia at diagnosis was a significant predictor for OS for the transplant cohort, while anemia at diagnosis gave a decreased risk of death. Hypercalcemia as well belonging to the older age groups (e.g., 61-70 years and 71-80 years) were significant predictors of death for the non-transplant patients (Table 2).ConclusionsFor MM patients in Norway, overall survival was much greater for patients receiving transplant in the first line. Hypercalcemia at diagnosis predicted death for both transplant and non-transplant cohorts and anemia at diagnosis was identified as a decreased risk of death for transplant patients, but not well-recorded for non-transplant patients. Belonging to an older age group (>71 or 80 years old) also was a significant predictor of death, but only for non-transplant patients. DisclosuresSchjesvold:Oncopeptides: Consultancy; Celgene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Honoraria; Bayer: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Novartis: Honoraria. Jenna:Janssen-Cilag: Other: Employee of StatFinn & EPID Research, contracted by Janssen-Cilag. Sõnajalg:Janssen-Cilag: Other: Employee of StatFinn & EPID Research, contracted by Janssen-Cilag. Leval:Janssen-Cilag: Employment. Rana:Janssen-Cilag: Employment. Castren-Kortekangas:Janssen-Cilag: Employment. Borgsten:Janssen-Cilag: Employment.

Impact of Acquired Del(17p) in Patients with Multiple Myeloma

Introduction Del(17p) detected by fluorescence in situ hybridisation (FISH) of bone marrow plasma cells (BMPCs) is an adverse prognostic factor in patients with multiple myeloma (MM). While the natural history and prognostic factors in patients with del (17p) detected at diagnosis have been studied, the outcomes of patients who acquire del (17p) later in their course are not known. We aimed to define the outcomes of MM patients who acquire del(17p). Methods We reviewed the Dysproteinemia database at Mayo Clinic, MN to identify 80 patients with MM who had their first FISH test negative for del (17p), but acquired del(17p) later in the course of the disease. Sixty (75%) patients had their first FISH within 6 months (mo) of diagnosis; 20 (25%) patients had their first FISH more than 6 mo after diagnosis of MM. Del(17p) included del(17p13.1) and/or monosomy 17. We identified 2 control patients for each case, who were diagnosed during the same time period, but did not demonstrate del (17p) at any time during follow-up. Results Characteristics of patients at acquisition of del(17p) are shown in Table 1. Of these, 76 patients had relapsed and/or refractory MM; in 4 patients, del (17p) was detected after having attained a response to prior therapy. Seventy (87.5%) patients had del (17p13.1); 5 (6.3%) patients had monosomy 17; 1 (1.2%) patient had both del (17p13.1) and monosomy 17. Four (5.0%) patients had relative loss of 17p. High-risk translocations (HRT) [t(4;14), t(14;16) and t(14;20)] were present in 14 (17.5%) patients. The percentage of PCs with del(17p) were available in 75 patients. The median percentage of PCs with del(17p) was 76 (range, 9-100). Sixty two (77.5%) patients received exclusively chemotherapy as subsequent treatment; stem cell transplant (SCT) was part of the next treatment in 16 (20%) patients (allogeneic SCT in 1). Among 71 evaluable patients, ≥very good partial response and ≥partial response were attained in 24 (33.8%) and 35 (49.2%) patients respectively. The median progression free survival (PFS) from detection of del (17p) was 5.7 mo (95% CI, 3.5-7.8); overall survival (OS) was 18.2 mo (CI, 13.1-27.5). From a comparable time point, the OS for 160 controls was 56.2 mo (CI, 37.1-75.3) (P We performed univariable analysis with variables at detection of del(17p) such as age ≥65 vs. 2 vs. ≤2 mg/dL, BMPC% ≥50 vs. Conclusion The prognosis of patients who acquire del (17p) is poor with OS of 6.5 years against 9 years from diagnosis in patients who do not acquire del (17p). This was valid across prognostic sub-groups. High PC proliferative rate was the only factor which impacted OS once patients acquired del(17p). Disclosures Kapoor:Celgene: Research Funding; Takeda: Research Funding. Gertz:Research to Practice: Consultancy; Teva: Consultancy; Ionis: Honoraria; annexon: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Apellis: Consultancy; Medscape: Consultancy; Amgen: Consultancy; janssen: Consultancy; celgene: Consultancy. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kumar:AbbVie: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity9s Board of Directors or advisory committees; KITE: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity9s Board of Directors or advisory committees; AbbVie: Membership on an entity9s Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding.