Early Infection Risk in Newly Diagnosed Multiple Myeloma Patients in the Modern Era

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3794-3794
Author(s):  
Ryan Stevenson ◽  
Diane M. Carpenter ◽  
Adnan Khan ◽  
Raleigh Fatoki ◽  
Sumanth Rajagopal ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
High Risk ◽  
Race And Ethnicity ◽  
The United States ◽  
Newly Diagnosed ◽  
Infection Rates ◽  
Community Based ◽  
The Past ◽  
Standard Risk

Abstract Background: Multiple myeloma (MM) is the second most common hematologic malignancy, with an estimated 30,000 new cases in the United States annually. Advances in management of MM over the past 20 years have significantly improved outcomes, but MM continues to be an incurable disease. Infections continue to be a major cause of morbidity and mortality, with a high proportion of MM patient developing infections within the first 3 months of diagnosis. There have been limited data on infection rates in MM patients in community-based oncology setting over the past two decades. This study looked to define infection rates and associated risk factors in newly diagnosed MM patients within 90 days of initial diagnosis. Methods: A retrospective, observational study was conducted on MM patients ages 18-89 newly diagnosed January 1, 2010-December 31, 2018 within Kaiser Permanente Northern California. Patients were required to have a minimum of one year of membership prior to MM diagnosis. SEER data was used to identify MM patients, and clinical data were extracted from the electronic health record. Bacterial, viral, and fungal infections were identified using ICD9/ICD10 codes. Baseline demographic and clinical characteristics from visit notes, laboratory and pathology results, and transplant data from utilization and claims data were analyzed to assess infection risks. High-risk cytogenetics was defined as notation of the following in pathology reports or oncology notes: add 1q, t(4:14), t(14:16), t(14:20), deletion of 17p. Bivariate analyses were conducted to assess differences across groups using the chi-squared test and the Wilcoxon-Mann-Whitney nonparametric test. Results: A total of 2030 newly diagnosed MM patients identified for this study. Median age at diagnosis was and n=828 (40.8%) of patients were female. Among this cohort, 522 (25.7%) had an infection within 90 days of MM diagnosis. The median age of patients having infections was 71 years (IQR 63-80), and the median age of those not having infections was 68 years (IQR 60-76, p<0.001). The median Charlson Comorbidity Index (CCI) of patients having infections was 3 (IQR 1-5) and the median CCI of those not having infections was 2 (IQR 1-4, p<0.001). Patients having hemoglobin <10.0 g/dl were more likely to have infection than those having hemoglobin >10.0 g/dl (30.4% vs. 23.6% respectively, p=0.011). Similarly, patients presenting with hypercalcemia (calcium >11.0 mg/dL) were more likely to have infection (37.4% vs. 24.6% in patients having calcium <11.0 mg/dL, p<0.001) as were patients with creatinine clearance <60.0 mL/min of those having <60.0 mL/min vs. 20.7% of those having >60.0 mL/min, p<0.001). Patients having indicators of high-risk cytogenetics were less likely to have infections within 90 days of diagnosis compared to those with standard risk cytogenetics (21.1% vs 26.2% respectively, p=0.031). We did not detect significant differences across transplant eligible status within the first year after diagnosis (22.1% infection among transplant eligible vs. 26.6% among those who were not transplant eligible, p=0.059) nor across sex (27.3% among females vs. 24.6% among males, p=0.176). Additionally, no significant differences in infection were detected across race and ethnicity (24.0% infection among Asian patients, 26.4% among Black patients, 27.7% among Hispanic patients, 25.5% among White patients, and 14.3% among patients having unknown or other race and ethnicity, p=0.741). Conclusions: In this community-based oncology study, infection within 90 days of diagnosis continues to be a significant complication of multiple myeloma and these results are comparable to previous studies. Risk factors for infection include age, CCI, standard risk cytogenetics, anemia, hypercalcemia, and renal failure. Stem cell transplant, sex and ethnicity were not associated with increased risk for infection. Future analysis will include assessments of hospitalization and mortality associated with infection. This study illustrates the importance of further research looking at decreasing infection rates in multiple myeloma patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Significance of Modified Risk Stratification Msmart 3.0 and Autologous Stem Cell Transplantation for Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5593-5593
Author(s):  
Andrey Garifullin ◽  
Sergei Voloshin ◽  
Vasily Shuvaev ◽  
Irina Martynkevich ◽  
Elizaveta Kleina ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Risk Stratification ◽  
Risk Group ◽  
High Risk Group ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Genetic Abnormalities ◽  
Standard Risk

Background The risk-stratification systems are repeatedly updated in accordance with the emergence of new information about the prognostic impact of anomalies and other factors. The most extensive and modern system in this time is mSMART risk stratification involving many parameters such as genetic anomalies, albumin, beta-2-microglobulin, LDH, Plasma Cell S-phase and GEP levels. It is possible to use risk-adapted treatment programs with or without ASCT. Nevertheless, the role of complex karyotype, combination of genetic abnormalities and ASCT remains unclear. Aims To estimate the genetic abnormalities in patients with newly diagnosed multiple myeloma and define the role of risk-stratification and ASCT in prognosis of disease. Methods The study included 159 patients (median age 63 years, range 28 - 83; male: female ratio - 1:1.37) with NDMM. Metaphase cytogenetics on bone marrow samples was done by standard GTG-method. FISH analyses were performed according to the manufacturer's protocol for detection primary IgH translocations, 13q (13q14/13q34) deletion, 1p32/1q21 amplification/deletion, P53/cen 17 deletion (MetaSystems DNA probes). We additional searched the t(4;14), t(6;14), t(11;14), t(14;16) and t(14;20) in patients with IgH translocation. All patient was treated by bortezomib-based programs (VD, CVD, VMP, PAD). ASCT was performed at 42% patients. Results The frequency of genetic abnormalities in NDMM patients was 49% (78/159). IgH translocation was detected in 26.4% (42/159) patients: t(11;14) - 16.3% (26/159), t(4;14) - 5.0% (8/159); TP53/del17p - 5.6% (9/159); 1p32/1q21 amp/del - 12% (19/159); hypodiploidy - 3.1% (5/159); hyperdiploidy - 1.25% (2/159); del5q - 0,6% (1/159); other - not found. Combination two aberrations was discovered in 11.9% (19/159) patients, complex abnormalities (>3 aberrations) - in 4.4% (7/159) patients. The median OS in "two aberration" and "complex abnormalities" groups were lower than in standard-risk mSMART 3.0 (normal, t(11;14), hypodiploidy, hyperdiploidy and other): 49 months, 26 months and was not reached, respectively (p=.00015). The median PFS for these groups was 12 months, 11 months and 30 months, respectively (p=.011). Differences between "two aberration" and "complex abnormalities" groups were not find (p> .05). We modified high-risk (gain 1q, p53 mutation, del 17p deletion, t(4;14), t(14;16), t(14;20), R-ISS stage III, double and triple hit myeloma) mSMART 3.0 by adding "two aberration" and "complex abnormalities" groups on based the OS and PFS results. The final analysis was based on the results of the complex examination of 87 patients: 53 patients in standard-risk group and 34 patients in high-risk group. The median OS in standard-risk mSMART 3.0 was not reached, in high-risk mSMART 3.0mod - 48 months; 5-years OS was 62% and 38%, respectively (p=0.0073). The median PFS was 43 and 29 months, respectively (p=.09). The best results of OS and PFS were reach in both groups of patient who performed ASCT. The median OS in standard-risk mSMART 3.0 with ASCT (n=37) was not reached, in high-risk mSMART 3.0mod with ASCT - 48 months (n=20); standard-risk mSMART 3.0 without ASCT - 40 months (n=16); in high-risk mSMART 3.0mod without ASCT - 22 months (n=14); 5-years OS was 81%, 60%, 33% and 28%, respectively (p=0.0015). The median PFS was not reached, 46, 22 and 19 months, respectively (p=.017). Conclusions The combination of two aberrations and complex abnormalities is unfavorable prognostic markers. The median OS and PFS was higher in standard-risk than high-risk group according mSMART 3.0mod. The ASCT can improve treatment's outcomes and life expectancy especially in patients with high-risk. It can be useful for update risk stratification in a future. Disclosures Shuvaev: Novartis: Consultancy; Pfize: Honoraria; Fusion Pharma: Consultancy; BMS: Consultancy.

Medullary Abnormalities in Appendicular Skeletons Detected With18F-FDG PET/CT Predict an Unfavorable Prognosis in Newly Diagnosed Multiple Myeloma Patients With High-Risk Factors

2019 ◽  
Vol 213 (4) ◽  
pp. 918-924 ◽  
Author(s):  
Yoshiaki Abe ◽  
Kentaro Narita ◽  
Hiroki Kobayashi ◽  
Akihiro Kitadate ◽  
Masami Takeuchi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
High Risk ◽  
Fdg Pet ◽  
Newly Diagnosed ◽  
High Risk Factors ◽  
Pet Ct ◽  
Fdg Pet Ct

Phase 2 Study of Carfilzomib, Thalidomide, and Low-Dose Dexamethasone As Induction/Consolidation in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma, the Carthadex Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1141-1141 ◽  
Author(s):  
Ruth Wester ◽  
Bronno van der Holt ◽  
Emelie Asselbergs ◽  
Mark van Duin ◽  
Sonja Zweegman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Induction Therapy ◽  
Research Funding ◽  
Fixed Dose ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
Standard Risk

Abstract Introduction A phase 2 dose escalation trial of Carfilzomib in combination with Thalidomide and Dexamethasone (KTd) for induction and consolidation in newly diagnosed, transplant-eligible patients with multiple myeloma (MM). We report the results of 4 dose levels. Methods In this multicenter, open-label, phase 2 trial, transplant-eligible patients aged between 18 and 65 years with previously untreated symptomatic MM were included. Patients were treated with 4 cycles of escalating dose of Carfilzomib + fixed-dose thalidomide and dexamethasone (KTd) for induction therapy. The dose of Carfilzomib was 20 mg/m2 i.v. on days 1, 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 and 16 of cycles 2 to 4. Thalidomide dose was 200 mg orally on days 1 through 28 and Dexamethasone 40 mg orally on days 1, 8, 15 and 22. Carfilzomib was escalated to 20/36 mg/m2 in cohort 2, to 20/45 mg/m2 in cohort 3 and to 20/56 mg/m2 in cohort 4. Induction was followed by stem cell harvest after Cyclophosphamide priming (2 to 4 mg/m2) and G-CSF. Hereafter patients received high-dose Melphalan (HDM, 200mg/m2) and autologous stem cell transplantation followed by consolidation treatment with 4 cycles of KTd in the same schedule except a lower dose of Thalidomide (50mg). The primary endpoint was response after induction therapy and overall, specifically complete response (CR) and very good partial response (VGPR). Secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS). Results All 111 patients with a median follow-up of 55, 42, 35 and 28 months, in cohorts 1 to 4, respectively were included in the analysis. Median age was 58 years. ISS stages I/II/III were 41%/34%/23%, respectively, R-ISS stages I/II/III/unknown were 23%/59%/9%/9%, respectively. Of 111 patients, 9 patients stopped treatment during/after induction, 8 patients after cyclophosphamide priming or HDM and 9 patients during consolidation because of toxicity (n=9), non-eligibility for further treatment (n=6), progression (n=5), refusal (n=2) or other reasons (n=4). Overall response rate for all cohorts was 95%. Response after induction was CR/sCR in 18% of patients, ≥ VGPR in 66% of patients, ≥ PR in 94% of patients. After HDM the CR/sCR rate increased to 31% and after consolidation to 64%. Responses between cohorts were in general comparable. See Table 1. Response based on risk status by ISS/FISH in either cohort and accumulated did not show a difference in CR/sCR rate after consolidation between standard-risk (67%) and high risk defined as t(4;14) and/or del17p and/or add1q and/or ISS3 (60%). OS at 30 months was comparable between standard risk and high risk, 91% versus 90%. PFS at 30 months for standard risk and high risk was 79% and 62%, logrank p=0.02 (HR=2.3, 95% CI=1.1-4.5). PFS at 30 months per cohort was 70% (95% CI, 55% to 81%), 70% (95% CI, 45% to 85%), 80% (95% CI, 56% to 92%) and 62% (95% CI, 32% to 82%) in cohorts 1,2, 3 and 4, respectively, and 71% (95% CI, 61% to 79%) in all patients. OS at 30 months per cohort was 90% (95% CI, 77% to 96%), 90% (95% CI, 66% to 97%), 95% (95% CI, 71% to 99%) and 88% (95% CI, 58% to 97%) respectively, and 91% (95% CI, 83% to 95%) in all patients. Gene expression profiling using the Affymetrix U133 Plus 2.0 GeneChips was performed on purified tumor cells for 49 patients. Using the prognostic classifier EMC92 a high-risk group of patients (16%) was identified versus standard risk (in terms of OS: logrank p=0.06 (HR=3.7, 95% CI=0.8-16.8), and in terms of PFS: logrank p=0.14 (HR=2.1, 95% CI=0.8-6.0)). Safety analysis for all 111 patients showed non-hematological grade 3 and 4 toxicity, mainly respiratory disorders (in 15%), GI disorders (13%) and skin lesions (10%). Toxicity between cohorts did not show a significant difference. Cardiac adverse events were limited and included heart failure (n=2 at 27 mg/m2), hypertension (n=2) and chest pain (n=1 at 45mg/m2). Conclusion Carfilzomib, thalidomide, dexamethasone (KTd) is an effective regimen, with increasing CR percentages following KTd consolidation. With escalated doses of Carfilzomib responses and toxicity were comparable to standard dose of 27 mg/m2. Disclosures Zweegman: Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kersten:Celgene: Research Funding; Amgen: Honoraria. Minnema:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Lokhorst:Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Broijl:Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Lower Plasma Mir-92a Levels Predict Shorter Progression-Free Survival In Newly Diagnosed Symptomatic Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1879-1879
Author(s):  
Seiichiro Yoshizawa ◽  
Tomohiro Umezu ◽  
Junko H Ohyashiki ◽  
Shinsuke Iida ◽  
Kazuma Ohyashiki
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Chromosomal Aberrations ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Newly Diagnosed ◽  
Lower Plasma ◽  
Free Survival ◽  
Cut Points ◽  
Standard Risk

Abstract Background Current prognostic model for multiple myeloma (MM) is based on International Staging System (ISS) and presence of specific chromosomal abnormalities (CAs), especially by fluorescence in situ hybridization (FISH) analysis. MicroRNAs (miRNAs) play important roles in the development and progression in multiple myeloma (MM). Previously, we have described that plasma miRNA profiling has showed considerably lower plasma miR-92a levels in newly diagnosed MM patients (Yoshizawa et al. Blood Cancer Journal 2(1):e53, 2012). The aim of this study was to investigate the impact of plasma miR-92a levels to CAs and to prognosis in patients with newly diagnosed MM. Patients and methods From April 2004 to December 2012, 60 patients with newly diagnosed symptomatic MM (median age, 66 years; range, 34-93 years) were included in this study. We measured plasma miR-92a values (miR-92a/miR-638) by qRT-PCR. They were divided into high-risk and standard-risk by using FISH and conventional cytogenetic studies: high-risk cytogenetics was defined as translocations t(4;14), t(14;16), or del (17p13) detected by FISH, or del (13q) by Q-banding according to IMWG guidelines. All others, including t(11;14), were defined as standard-risk cytogenetics. We analyzed the clinical relevance of plasma miR-92a levels with respects to CAs. Furthermore we identified miR-92a expression cut points with the most impact on outcome to investigate which of the some disease characteristics and its cut-off value had prognostic influence in MM patients. Results Chromosomal aberrations were noted in 26 (43%) MM patients after diagnosis, including 12 patients with t(4;14), 5 with t(11;14), 3 with t(14;16), 2 with del (17p13), 2 with del (13q), and 1 with t(4;14) and del (17p13), 1 with t(11;14) and del (17p13). Between MM patients with and without high-risk cytogenetics, there were no significant differences in β2-microglobulin and albumin levels (P = 0.994 and 0.85, respectively), ISS staging (P = 0.583), age (P = 0.651), sex (P = 0.585), frequency of CRAB symptoms (hypercalcemia, P = 0.755; renal insufficiency, P = 0.75; anemia, P = 0.375; bone lesion, P= 0.65, respectively). The plasma miR-92a level was significantly lower in the newly diagnosed MM with high-risk groups than in those with standard-risk groups (P = 0.015). Patients with plasma miR-92a levels < 0.04 had a significantly shorter progression-free survival (PFS) than patients with plasma miR-92a levels ≥ 0.04 (median PFS: 48 vs 15.8 months, P = 0.011). In addition, some clinical parameters were associated with adverse PFS: high-risk cytogenetics (P = 0.001), high proportions of bone marrow plasma cells (P = 0.043), high levels of serum β2-microglobulin (P = 0.022) and not attaining ≥ very good partial response (VGPR) (P = 0.007). On multivariate analysis, lower miR-92a level was an independent prognostic factor for PFS. Using the same miR-92a cut points, there was a tendency towards significant difference among standard-risk myeloma patients (P = 0.077). Moreover, the combinations of chromosomal aberrations and plasma miR-92a were able to classify newly diagnosed MM patients with three risk groups with different probabilities. Conclusion The plasma miR-92a values vary across high- and standard-risk cytogenetics in newly diagnosed MM patients. We conclude that measurement of plasma miR-92a levels may not only function as novel biomarkers for diagnosis, but may also be helpful for prognostic stratification. Disclosures: Ohyashiki: Janssen Pharmaceutical co.: Research Funding.

scholarly journals Efficacy of Upfront Daratumumab Combination Regimen in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3158-3158 ◽  
Author(s):  
Kyaw Zin Thein ◽  
Thura Win Htut ◽  
Myint Aung Win ◽  
Sriman Swarup ◽  
Anita Sultan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Novel Agents ◽  
Combination Regimen ◽  
Newly Diagnosed ◽  
Standard Risk

Introduction: Management of newly diagnosed multiple myeloma (NDMM), which accounts for 1% of all cancers, is an area in dire need of therapeutic innovation. In recent years, the introduction of novel agents is one of the major advances in the management of patients with NDMM, in both transplant- eligible and transplant- ineligible candidates. Studies have combined daratumumab, a human IgGκ monoclonal antibody that targets CD38 which is highly expressed on myeloma cells, with proteasome inhibitors and immunomodulatory agents-based regimens in the first-line treatment of NDMM. The purpose of our study is to explore and consolidate the efficacy of upfront daratumumab combination regimen in patients with NDMM. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with newly diagnosed/ untreated multiple myeloma were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) for overall response rate (ORR), including stringent complete response (sCR), CR and very good partial response (VGPR). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. Results: Three phase III RCTs with a total of 2,528 patients with NDMMwere included.Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, and DVd + thalidomide (T) vs VTd. The randomization ratio was 1:1 in all studies. The I2statistic for heterogeneity was 0, suggesting homogeneity among RCT. The pooled HR for PFS was statistically significant at 0.52 (95% CI: 0.44-0.61; P < 0.0001). The PFS benefit was observed in all ISS categories, types of immunoglobulin (Ig) and standard risk cytogenetic; ISS I cohort (HR, 0.55; 95% CI: 0.37- 0.82; P = 0.003), ISS II cohort (HR, 0.43; 95% CI: 0.33- 0.55; P < 0.0001), ISS III cohort (HR, 0.63; 95% CI: 0.48- 0.82; P = 0.0006), IgG cohort (HR, 0.56; 95% CI: 0.40- 0.77; P = 0.0003), non-IgG cohort (HR, 0.52; 95% CI: 0.28- 0.97; P = 0.04), and standard risk cytogenetic cohort (HR, 0.43; 95% CI: 0.35- 0.53; P < 0.0001). The pooled HR for PFS in high risk cytogenetic cohort was not statistically significant at 0.76 (95% CI: 0.53- 1.10; P = 0.15). The pooled RR for ORR was 1.13 (95% CI: 1.01-1.26; P = 0.03), sCR was 2.02 (95% CI: 1.33-3.08; P = 0.001), CR was 1.46 (95% CI: 1.20-1.79; P = 0.0002),and VGPR was 1.01 (95% CI: 0.82-1.25; P = 0.93). The pooled RR for negative minimal residual disease (MRD) was 2.54 (95% CI: 1.24-5.20; P = 0.01). Conclusions: Upfront combination regimen with daratumumab significantly improved PFS, ORR, sCR and CR along with negative MRD, compared to control arm in patients with NDMM. The improvement in PFS was noted across all subgroups except in high-risk cytogenetic group. More randomized studies are required to explore further novel agents and to formulate optimal combination regimen to improve survival in this high-risk cytogenetic subset. Disclosures No relevant conflicts of interest to declare.

scholarly journals Abnormal Metaphase Cytogenetics Adds to Currently Known Risk-Factors for Venous Thromboembolism in Multiple Myeloma: Derivation of the PRISM score

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Rajshekhar Chakraborty ◽  
Lisa Rybicki ◽  
Jason Valent ◽  
Alex V. Mejia Garcia ◽  
Beth M. Faiman ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
High Risk ◽  
Research Funding ◽  
Treatment Initiation ◽  
Newly Diagnosed ◽  
Prism Score ◽  
C Statistic ◽  
The Impact ◽  
Disease Specific

Background: Prevention and management of venous thromboembolic events [VTE] is an important component of supportive care in newly diagnosed multiple myeloma [MM], especially in the era of immunomodulatory drugs [IMiDs]. Recently, two validated risk assessment models [RAMs], SAVED and IMPEDE-VTE, were developed to identify patients at high risk of VTE. However, these models have following limitations: (1) Patients were not uniformly treated in the era of contemporary MM therapy (2) Disease-specific variables were not available in the databases from which these scores were derived. Our primary aim was to develop a simple predictive model for VTE in MM using patient-specific, disease-specific, and treatment-specific variables. Our secondary aim was to assess the impact of VTE on overall survival [OS]. Methods: All consecutive patients with newly diagnosed MM treated at Cleveland Clinic from 1/1/2008 to 12/31/2018 were included in our analysis. The primary objective was to identify baseline variables associated with VTE within 12 months of treatment initiation. Candidate variables included those in IMWG, SAVED, and IMPEDE-VTE models as well as additional risk-factors from literature review in MM and cancer-associated VTE. Stepwise selection with variable entry criterion of p&lt;0.20 and a variable retention criterion of p&lt;0.05 was used to identify significant factors on multivariable analysis [MVA]. RAM was developed by subtracting 1 from the hazard ratio of a potential variable, rounding to the nearest 0.5, and multiplying by 2 to obtain a whole number. The impact of VTE on OS was assessed with landmark analysis. Results: A total of 934 patients with newly diagnosed MM and available data on VTE occurrence were considered for inclusion. We excluded patients with VTE within 6 months before starting therapy [n=5] and patients on therapeutic anticoagulation or receiving &gt;1 prophylactic regimen [n=146], resulting in a total of 783 patients for model development. The most common induction regimen was bortezomib [V]-lenalidomide [R]-dexamethasone [VRD; 41%], followed by VD [22%], RD [20%], V-cyclophosphamide-dexamethasone [VCD; 11%], and others [7%]. Median age at treatment initiation was 63 years [range, 22-91], 55% were males, and 20% were Blacks. ISS stage III disease was present in 32%, high-risk FISH in 23%, abnormal metaphase cytogenetics in 18%, and serum creatinine &gt;2 mg/dl in 19% of patients. Notably, 76% had received a dexamethasone dose of 120-160 mg/cycle, with only 5.9% started on a higher dose [&gt;160 mg/cycle]. The most common thromboprophylaxis agent was aspirin [60%], followed by low molecular weight heparin [LMWH; 3.8%]; 37% of patients received no thromboprophylaxis. Erythropoietin and intravenous immunoglobulin were used in 2.9% and 1.2% of patients respectively. Median time to VTE from treatment initiation was 3.2 months. Cumulative incidence of VTE at 6 and 12 months was 8.2% [95% CI, 6.6-10.1] and 11.5% [95% CI, 9.5-13.6] respectively. Factors significantly associated with development of VTE on MVA were combined to develop the PRISM score [Table 1]: Prior VTE history [HR 5.06; 8 points], Black Race [HR 1.71; 1 point], IMiD use [HR 2.17; 2 points], Surgery within 3 months [HR 3.44; 5 points], and abnormal Metaphase cytogenetics [HR 2.10; 2 points]. The theoretical score range is 0-18, with a HR of 1.28 per 1-point increase in score [c-statistic 0.62]. Internal bootstrap validation including 1,000 samples showed a c-statistic of 0.62 [IQR, 0.60-0.64]. Using three risk groups by recursive partitioning analysis, 17.8%, 74%, and 8.1% belonged to low [0], intermediate [1-6], and high-risk [&gt;6] groups respectively. The 12-month cumulative incidence of VTE in the 3 respective groups were 2.7%, 10.8%, and 36.5% [Figure 1]. Occurrence of VTE in the first 12 months was not associated with worse OS on landmark analysis at 3, 6, 9, and 12 months. Conclusion: We have developed and internally validated a RAM for VTE in MM in the context of contemporary MM therapy including disease-specific variables. Studies of external validation and comparison with existing RAMs are warranted. The PRISM Score could be used to identify high-risk patients for thromboprophylaxis. Figure Disclosures Valent: Amgen Inc.: Other: Teaching, Speakers Bureau; Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau. Khouri:Sanofi Genzyme: Other: Advisory Board. Anwer:Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Khorana:Pharmacyclics: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Medscape: Honoraria; Leo Pharma: Honoraria; Seattle Genetics: Honoraria; Pharmacyte: Honoraria; Leap: Research Funding; Bayer: Honoraria; Janssen: Honoraria; Merck: Research Funding; Array: Other: Research funding (to institution); BMS: Honoraria, Research Funding.

Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance

Blood ◽  
2011 ◽  
Vol 118 (17) ◽  
pp. 4547-4553 ◽  
Author(s):  
María-Victoria Mateos ◽  
Norma C. Gutiérrez ◽  
María-Luisa Martín-Ramos ◽  
Bruno Paiva ◽  
María-Angeles Montalbán ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Dna Ploidy ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Cytogenetic Abnormalities ◽  
High Risk Patients ◽  
Risk Patients ◽  
Standard Risk

Abstract Cytogenetic abnormalities (CAs) such as t(4;14), t(14;16) or del(17p), and nonhyperdiploidy are associated with poor prognosis in multiple myeloma. We evaluated the influence of CAs by FISH and DNA ploidy by flow cytometry on response and survival in 232 elderly, newly diagnosed multiple myeloma patients receiving an induction with weekly bortezomib followed by maintenance therapy with bortezomib-based combinations. Response was similar in the high-risk and standard-risk CA groups, both after induction (21% vs 27% complete responses [CRs]) and maintenance (39% vs 45% CR). However, high-risk patients showed shorter progression-free survival (PFS) than standard-risk patients, both from the first (24 vs 33 months; P = .04) and second randomization (17 vs 27 months; P = .01). This also translated into shorter overall survival (OS) for high-risk patients (3-year OS: 55% vs 77%; P = .001). This adverse prognosis applied to either t(4;14) or del(17p). Concerning DNA ploidy, hyperdiploid patients showed longer OS than nonhyperdiploid patients (77% vs 63% at 3 years; P = .04), and this was more evident in patients treated with bortezomib, thalidomide, and prednisone (77% vs 53% at 3 years; P = .02). The present schema does not overcome the negative prognosis of high-risk CAs and nonhyperdiploidy. This trial was registered with www.ClinicalTrials.gov as NCT00443235.

Prospective study to measure the impact of MMprofiler on treatment intention in newly diagnosed multiple myeloma patients (PROMMIS).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8030-8030
Author(s):  
Parameswaran Hari ◽  
Suzanne Lentzsch ◽  
David Samuel DiCapua Siegel ◽  
Saad Zafar Usmani ◽  
Binod Dhakal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Risk Classification ◽  
Newly Diagnosed ◽  
Treatment Paradigm ◽  
Risk Patients ◽  
The Impact ◽  
Standard Risk

8030 Background: Multiple Myeloma (MM) is recognized as a heterogeneous group of patients with varying response and outcome of their disease, associated with various risk factors including genetic aberrations. Risk adapted treatment strategies are beginning to emerge (e.g. mSMART), which include gene expression signatures. SKY92, a 92-gene prognostic signature, classifies MM patients as “high” or “standard” risk. It has been reported to be a robust predictor for Overall and Progression Free Survival (Kuiper 2012, 2015). Here we report the preliminary impact of SKY92 on risk classification and treatment intention decisions in newly diagnosed MM patients enrolled in the PRospective Observational Multiple Myeloma Impact Study (PROMMIS). Methods: Patients with MM had their BM aspirate analyzed using the MMprofiler with SKY92. The physician completed questionnaires with his/her treatment intention, before and after knowing SKY92 results. Results: 39 MM patients were enrolled from 5 US centers. The SKY92 signature classified 15 patients (38%) as high risk. Prior to knowing SKY92 results, physicians regarded 20 (51%) patients as clinically high risk, for whom SKY92 indicated 12 patients to be standard risk. Upon revealing SKY92, 8 patients were then considered standard risk by the physician. For 2 patients with concordant high risk classification results, the confirmation of the risk classification was considered helpful. The impact of treatment intention decisions in clinical high risk patients was 40% (8 out of 20). In the 19 patients (49%) that were regarded clinically standard risk prior to knowing SKY92, SKY92 indicated 7 patients to be high risk. Physicians agreed to this classification. For 4 patients with concordant risk classification, the confirmation was found helpful. The impact of treatment intention decisions in clinical standard risk patients was 37% (7 out of 19). Conclusions: Preliminary results from the PROMMIS trial indicate that SKY92 impacts the physician’s treatment intention for 38% of patients with newly diagnosed MM. Moreover, the physicians found the SKY92 result useful for 54% of the patients. This underlines the relevance and need for assessment of SKY92 in MM patients, and associated risk stratified treatment paradigm. Clinical trial information: NCT02911571.

scholarly journals Multiple myeloma immunoglobulin λ translocations portend poor prognosis

2018 ◽  
Author(s):  
Benjamin G. Barwick ◽  
Paola Neri ◽  
Nizar J. Bahlis ◽  
Ajay K. Nooka ◽  
Jonathan L. Kaufman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Transcription Factor ◽  
High Risk ◽  
Poor Prognosis ◽  
Plasma Cells ◽  
Whole Genome ◽  
Newly Diagnosed ◽  
Myeloma Cells ◽  
Current Therapies ◽  
Standard Risk

AbstractMultiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed ‘high-risk’. To better understand and identify high-risk myeloma, we analyzed the translocation landscape of 826 newly-diagnosed patients by whole genome sequencing as part of the CoMMpass study. Translocations at the IgL locus were present in 10% of myeloma patients, and corresponded with poor prognosis. Importantly, 70% of IgL translocations co-occurred with hyperdiploid disease, a marker of standard risk, which is routinely diagnosed clinically whereas IgL-translocations are not. Thus, it is likely that the majority of IgL-translocated myeloma is being misclassified. The IgL enhancer is among the strongest in myeloma cells, indicating it can robustly drive oncogene expression when translocated. Consistent with this, IgL-translocated patients failed to benefit from immunomodulatory imide drugs (IMiDs), which target the lymphocyte-specific transcription factor Ikaros. These data implicate the IgL enhancer as resistant to IMiD-inhibition, and when translocated, as a driver of poor prognosis.

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