Sars Cov-2/COVID-19 in Multiple Myeloma Latin-American Patients COVID-Lamm Study on Behalf of Gelamm (Grupo de Estudio Latino- Americano de Mieloma Múltiple)

Background The SARS CoV-2 / COVID 19 pandemic has challenged the world's health systems, especially services that treat cancer. The first studies in China showed that cancer patients had a higher risk of becoming infected and dying. Other risk factors for mortality were age over 65 years, male sex, the presence of comorbidity, hypertension, cardiovascular disease, diabetes, and obesity. Data on the specific behavior of patients with multiple myeloma (MM) in the pandemic are scarce. The mechanisms by which MM patients may have a higher mortality are multiple, derived both from the disease itself due to cellular and humoral immunity deficiency as well as from anti-myeloma treatment. The present study aims to establish the behavior of the disease in the pandemic period in Latin America. Methods This is a retrospective case series of in and outpatients with a diagnosis of MM and COVID-19 reported from centers from Latin America between March and July 31, 2020. The analysis of demographic, clinical, laboratory, complications and therapy variables were done using descriptive statistics. A Kaplan Meier survival analysis was performed, with Log Rank statistic. Finally, a Cox regression was performed to identify independent risk factors of worse outcome. Pre-admission characteristics, MM status, and comorbidities constituted the reference model and were used to adjust the association of relevant MM characteristics with mortality. Program used for analysis was SPSS statistics 25. Results Fifty-two patients with COVID-19 and MM from 7 countries were included. Demographic characteristics, comorbidities, infection baseline clinical conditions, treatment, and outcomes are shown in Table 1. The characteristics in terms of MM status are shown in Table 2. When performing the survival analysis, it is evidenced that the survival of the entire cohort at day 49 was 67% Figure 1. When we focus on patients with comorbidities, survival drops to 53.5% +/- 10.6 (CI 95% 53.4 - 99.4 and p value of 0.041) for the same day Figure 2. When performing the obesity analysis, a drop in survival of up to 39% was observed (95% CI 24.448 - 56.76, with p = 0.00001) Figure 3. Adjusted HR for obesity is 5,078 (95% CI 1,389-18,558, α0.014) and mechanical ventilation with a HR of 3,943 (95% CI - 1,296 - 11,998, α0.016) When comparing patients with controlled MM (> PR) versus uncontrolled, the mortality rate was 84% versus 58% respectively (p = 0.109). Comorbidities (presence of either diabetes, arterial hypertension, cardiovascular disease, or "others"), obesity, need of mechanical ventilation, and <VGPR at the time of infection were independent factors of lower survival Table 3. Conclusions Patients with MM and COVID-19 has an overall mortality of approximately 30% and this is strongly influenced by the presence of comorbidities, uncontrolled disease and need of mechanical ventilation. Survival of patients without comorbidities and controlled disease is good, suggesting that this group of patients would not require modification of MM therapy. The main limitations of our study are its retrospective nature and the low number of patients. It must be highlighted that at the time of the analysis most of Latin American countries were still in the peak of the pandemic. Prospective studies are required to elucidate the behavior of these risk factors in mortality, to optimize the management of patients with MM in this period of the SARS CoV-2 / COVID-19 pandemic. Disclosures Peña: BindingSite: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau. Abello:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Takeda: Honoraria, Research Funding; Dr. Reddy's: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Idrobo:Abbvie: Honoraria, Speakers Bureau; Tecnofarma: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Rojas:Novartis: Consultancy; Roche: Honoraria; Sandoz: Honoraria; Abbvie: Honoraria. Remaggi:Takeda: Honoraria; Raffo Argentina: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gador Argentina: Research Funding; Amgen: Honoraria, Research Funding. Alvarado:Celgene: Speakers Bureau; Alexion: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau; Roche: Speakers Bureau. De la Peña-Celaya:Amgen: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau. Perez:Novartis: Speakers Bureau; Celgene: Speakers Bureau; Roche: Speakers Bureau.

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Treatment Outcomes of Real Life Elderly Multiple Myeloma Patients:Â Analysis from Registry of Monoclonal Gammopathies (RMG)

Blood ◽

10.1182/blood-2018-99-111882 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2019-2019

Author(s):

Jakub Radocha ◽

Roman Hajek ◽

Lucie Brozova ◽

Ludek Pour ◽

Ivan Spicka ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Overall Survival ◽

Treatment Outcomes ◽

Board Of Directors ◽

Research Funding ◽

Statistical Significance ◽

Real Life ◽

Advisory Committees ◽

Monoclonal Gammopathies

Abstract Introduction: Multiple myeloma patients over the age of 65 represent the majority of myeloma population. The main goal was to evaluate treatment outcomes in terms of overall survival for elderly patients based on initial choice of anti-myeloma drugs, and to find potential factors affecting survival. Patients and Methods: This is a retrospective registry based analysis from the Registry of monoclonal gammopathies of the Czech Myeloma Group. Patients with multiple myeloma diagnosed between 2007-2016 over the age of 65 with symptomatic myeloma were included in the analysis. Basic demographic data and disease characteristics were obtained. The Kaplan-Meier estimates were completed by the Greenwood confidence interval. The log-rank test was used to estimate the statistical significance of the difference between the curves. The Cox proportional hazards model was performed to explore the univariate significance of risk factors. Results: Data from 1410 MM patients were obtained. Gender [HR 1.316 (1.124-1.541), p=0.001], age [above 75 vs. 66-75, HR 1.437 (1.221-1.692), p< 0.001], creatinine levels [at cutoff 152 µmol/L, HR 1.613 (1.365-1.905), p< 0.001] and ECOG performance status [0-1 vs. 2-4, 1.869 (1.594-2.191), p< 0.001] were found to significantly affect overall survival. Moreover these risk factors have cumulative effect on overall survival of the patients. Overall survival of patients regardless to above mentioned risk factors treated with upfront bortezomib (N = 880) was median OS 40.4 months (CI: 36.1-44.7), patients treated with upfront thalidomide (N = 370) had median OS 48.1 months (CI: 41.0-55.2), for lenalidomide (N = 64) median overall survival was 53.2 months (CI: 44.6-61.8) and for combination of bortezomib and thalidomide (N = 46) 32.2 months (CI: 26.6-37.8). When any of these risk factors was present the OS in each group shortened. In the group of patients with no risk factors (N = 255) the median OS for bortezomib (N = 126) was not reached, for thalidomide (N = 96) the median OS was 66.3 months (CI: 43.1-89.6), for lenalidomide (N = 17) 71.1 months (CI: 44.8-97.4) and for combination of bortezomib and thalidomide (N=8) was not reached. In the group of patients with 1 risk factor (N = 514) the median OS for bortezomib (N = 303) was 46.1 months (CI: 36.2-56.1), for thalidomide (N = 141) 56.2 months (CI: 47.5-64.9), for lenalidomide (N = 29) 49.0 months (CI: 9.7-88.2) and for combination of bortezomib and thalidomide (N=20) was not reached. In the group of patients with 2 risk factors (N = 420) the median OS for bortezomib (N = 288) was 34.0 months (CI: 24.7-43.4), for thalidomide (N = 87) 31.9 months (CI: 22.8-40.9), for lenalidomide (N = 14) 33.2 months (CI: 0.0-67.6) and for combination of bortezomib and thalidomide (N=20) 29.4 months (CI: 7.6-51.1). In the group of patients with 3-4 risk factors (N = 221) the median OS for bortezomib (N = 163) was 19.2 months (CI: 14.9-23.5), for thalidomide (N = 46) 18.9 months (CI: 13.0-24.7), for lenalidomide (N = 4) 6.1 months (CI: 0.0-63.0) and for combination of bortezomib and thalidomide (N=3) 14.3 months (CI:-). Conclusion: The overall survival of patients above the age of 65 shows promising results with the use of novel agents. The treatment outcomes seem to be generally affected by overall condition, age and gender of the patient rather than treatment modality used upfront. Figure. Figure. Disclosures Hajek: Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Maisnar:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

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Obesity In Young Adulthood Is Associated With Early Onset Multiple Myeloma In African Americans

Blood ◽

10.1182/blood.v122.21.1872.1872 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1872-1872

Author(s):

Amie E. Hwang ◽

Sikander Ailawadhi ◽

Leon Bernal-Mizrachi ◽

Todd M Zimmerman ◽

Christopher Haiman ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

African American ◽

African Americans ◽

Board Of Directors ◽

Research Funding ◽

Clinical Characteristics ◽

Age At Diagnosis ◽

Advisory Committees ◽

Younger Age

Abstract Introduction African-American ethnicity, male sex, older age and obesity are accepted risk factors for multiple myeloma (MM). Obesity early in life is a risk factor for many cancers, including MM; most studies have focused on populations of European origin. African-Americans have a higher prevalence of obesity than other populations, and may have a distinct genetic contribution to this condition. We established a multi-center collaborative study to investigate possible explanations for the excess risk of MM among African-Americans. The aim of the present case-case analysis was to determine whether body mass index (BMI) was associated with risk factors and clinical characteristics at presentation in African-American MM patients. Methods Patients diagnosed with active MM since January 1, 2009 were recruited from nine outpatient centers and three Surveillance, Epidemiology, End-Results Program (SEER) population-based cancer registries. Information on weight and height at 20 years of age and at 5 years prior to diagnosis was obtained from questionnaires. Clinical information collected included age at diagnosis, stage, percent plasmacytosis on bone marrow biopsy, β2 microglobulin level, Ig serotype, light vs. heavy chain disease, and presence of lytic bone lesions. BMI (ht/wt2) was categorized into 3 levels (normal <25, overweight 25-29, obese >30) according to World Health Organization standard. The Pearson chi-square test was used to test the association between BMI category, and risk factors and clinical characteristics. Mean ages at diagnosis across BMI categories were compared using linear regression and a t-test for trend calculated. Results To date, 1,044 African-American MM patients have been enrolled and of those, 1,014 provided a DNA sample. At present, 970 patients have completed a questionnaire, clinical records have been abstracted for 823 patients, and 509 patients have some information on gender, age at diagnosis, weight, height and clinical characteristics.The mean age at diagnosis was 59. Increasing BMI at age 20 was associated with younger age at diagnosis (p= 0.0004), whereas BMI at 5 years prior to diagnosis was not associated with age at diagnosis (p=0.9477). Among men, mean age at diagnosis decreased with increasing BMI at age 20 (p= 0.0125) (Table 1a) and at 5 years prior to diagnosis (p=0.0252) (Table 1b). Among women, the trend was signficant at age 20 (p=0.0018) (Table 1a) but not at 5 years prior to diagnosis (p= 0.7094) (Table 1b). Increasing BMI was not significantly associated with any other clinical characteristics. Conclusion/Discussion In a large collection of African-American MM patients, we observed a strong association between increasing BMI at age 20 and younger age at diagnosis. A similar trend was observed in men only at 5 years prior to diagnosis, consistent with previous reports. Obesity is one of the few known potentially modifiable risk factors for MM. Younger age at diagnosis reflects an earlier accumulation of either or both genetic and environmental risk factors. Obesity at an early age may influence MM risk through shared biological pathways such as interleukin-6 and insulin-like growth factor, by contributing to chronic B-cell activation, thereby increasing susceptibilty for MM later in life. The significance of the gender difference for the association closer to diagnosis is unclear and requires additional study. Disclosures: Terebelo: Amgen: Honoraria; Millennium: Honoraria. Mehta:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Zonder:Skyline: Consultancy. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Lonial:Celgene Corporation: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

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Using Current Clinical Markers to Define High Risk Smoldering Multiple Myeloma: Agree to Disagree

Blood ◽

10.1182/blood-2019-126952 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1794-1794

Author(s):

Elizabeth Hill ◽

Neha Korde ◽

Sham Mailankody ◽

Candis Morrison ◽

Alexander Dew ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Bone Marrow ◽

Clinical Trials ◽

Board Of Directors ◽

Mayo Clinic ◽

Research Funding ◽

M Protein ◽

Advisory Committees ◽

Rate Of Progression

Introduction Defining high risk (HR) smoldering multiple myeloma (SMM) is becoming increasingly important as multiple clinical trials are actively investigating the role of early treatment. On average, patients with SMM progress to multiple myeloma (MM) at a rate of 10% per year for the first 5 years (Kyle 2007). Several classification systems have been developed to identify patients with a higher rate of progression, including two commonly used models: the 2008 Mayo Clinic model and the PETHEMA (Programa de Estudio y Tratamiento de las Hemopatias Malignas) model. The 2008 Mayo Clinic model incorporates M-protein (>3 g/dL), bone marrow plasma cell percentage (BMPC%) >10%, and a ratio of involved to uninvolved serum free light chains (sFLCr) >8. Patients with all three characteristics had a 76% risk of progression to MM in 5 years (Dispenzieri 2008). The PETHEMA model uses the proportion of BMPCs with aberrant plasma cell phenotype on flow cytometry (>95%) and reduction in uninvolved immunoglobulins (immunoparesis) to identify HR patients. Patients with both risk factors had a 5-year rate of progression to MM of 72% (Perez-Persona 2007). The 2008 Mayo Clinic model was validated prior to the International Myeloma Working Group reclassification of MM in 2014. Therefore, in 2018, Mayo Clinic proposed a new model to define HR SMM referred to as "2/20/20": M-protein >2 g/dL, BMPC% >20%, and sFLCr >20 (Lakshman 2018). The median time to progression for the HR group (2-3 risk factors) was 29 months, compared to 110 months in the low risk (LR) group (0 risk factors). Previously, a high discordance rate among the 2008 Mayo model and the PETHEMA model was reported (Cherry 2013). In this study, we aim to define the concordance among patients defined as HR SMM by the aforementioned models in an independent sequential patient cohort. Methods The medical records of patients sequentially assigned a diagnosis of SMM by the myeloma program at the NIH Clinical Center between April 2010 to July 2019 were reviewed. Patients with myeloma defining events were excluded (i.e. MM). Each patient was assigned a risk score based on the 2008 Mayo Clinic model, the 2018 Mayo Clinic model, and the PETHEMA model. The distribution of patients in the LR, intermediate (IR), and HR groups were compared between the models. Concordance ratios were calculated between the three models. Results A total of 236 patient records were reviewed and per the 2014 IMWG criteria, 138 patients were identified as having SMM. Two patients did not have bone marrow flow cytometry samples and thus could not be classified by the PETHEMA model. Therefore, 136 patients were stratified by risk based on all three models (Table 1,2). The rate of concordance between the 2008 Mayo Model and the PETHEMA model was 31.6% (95% CI: 24.4-39.8%), similar to previously published results. The concordance between the 2018 Mayo Model and the PETHEMA model was slightly higher at 44.8% (95% CI: 36.7-53.2%; P=0.0337). There was significant discordance between the models in classifying patients as HR versus non-HR (Table 3). However, the 2018 Mayo Clinic model had a higher concordance with the PETHEMA model (27.2%; 95% CI: 20.4-35.3%) than the 2008 Mayo Clinic model (4.4%; 95% CI:1.8-9.5%). Conclusions The accurate identification of SMM patients at highest risk of developing MM remains elusive and no one model has been found to be superior than the other. As this study indicates, a significant number of patients may be classified as "HR" according to the PETHEMA model while simultaneously be defined as "LR" based on the Mayo Clinic models. While the 2018 Mayo Clinic model has a higher concordance rate to the PETHEMA model, it remains significantly discordant. These results indicate that the current clinical variables used to determine risk are not reliable. This is likely due to the fact that they are markers of disease burden rather than biology and risk is subject to increase over time (Landgren 2019). It is time for genomic signatures which signify varying biology to be incorporated into risk models. The treatment of HR SMM is currently being investigated in multiple clinical trials. As the results from these trials are published, the data will need to be scrutinized as to how patients were defined as "HR" in order to compare results. At this time, it remains unclear which patients warrant early intervention and it is imperative that patients with SMM be exclusively treated on clinical trials. Disclosures Mailankody: Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Landgren:Merck: Other: IDMC; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Risk Factors Associated with Development of Extramedullary Disease in Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-114854 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5596-5596

Author(s):

Martin Stork ◽

Sabina Sevcikova ◽

Marta Krejci ◽

Zdenek Adam ◽

Viera Sandecka ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Poor Prognosis ◽

First Line ◽

Advisory Committees ◽

Line Of Therapy

Abstract Background Multiple myeloma (MM) is the second most common hematological malignancy characterized by plasma cell (PC) infiltration of the bone marrow. Unfortunately, better imaging techniques convey multiple reports about increased incidence of the so-called extramedullary disease of MM (EM), an aggressive, mostly resistant entity with poor prognosis for patients. EM probably develops because of 'bone marrow escape' of PC subclone that migrates out of the BM infiltrating soft tissues losing dependence on the BM microenvironment, either partially or completely. There are two types of EM - primary, found at the time of MM diagnosis, and secondary, found at the time of MM relapse. However, there are very few reports about EM. Aims This study aims to analyze risk factors connected to EM development. Methods Data from the Registry of Monoclonal Gammopathies (RMG) were analyzed. The RMG represents a database for collection of clinical data concerning diagnosis, treatment and follow-up of Czech MM and other monoclonal gammopathies patients. In total, data of 4985 MM patients were collected into the RMG database between 2007 and June 2017. Our analysis compared patients who developed EM at initiation of first or higher line of therapy with patients without EM during at least 5-year-long follow-up (patients who died earlier included). Logistic regression analysis was used to assess the association of baseline characteristics at MM diagnosis with EM occurrence at first line and relapse, respectively. Results In total, 4985 MM patients data were collected into the RMG database between 2007 and 2017. Patients were treated with bortezomib, lenalidomide, thalidomide, pomalidomide, ixazomib and daratumumab. Regardless of treatment, EM patients responded worse than MM patients did to any form of treatment. While primary EM patients had similar PFS as MM patients, OS was significantly worse (48.7 vs 60.6 months, resp.). Secondary EM patients did even worse, with PFS 8.7 months and OS 23.8 months only. We found 543 MM patients (10.9%) who developed EM during the entire follow-up. Out of these EM patients, we found 309 patients who were diagnosed with primary EM at initiation of first line of therapy. At initiation of 2nd line of treatment, we found 111 secondary EM patients. At 3rd, 4th and 5th, we found 61, 39 and 23 EM patients, resp. Finally, 309 patients who developed EM at initiation of 1st line and 234 patients who developed EM at initiation of further treatments were compared to 2092 patients who did not develop EM during the entire course of the disease. Overall, occurrence of EM at 1st or higher lines of treatment was associated with younger age, male sex, low ISS, D-S substage A, low B2 microglobulin, low creatinine, high hemoglobin, elevated thrombocytes, other types of M-Ig than IgG and presence of bone lesions. For EM cases found only at initiation of 1st line (primary EM), we found association with high ECOG status, low LDH, low M-protein quantity and low % of plasma cells infiltration in the bone marrow. For EM cases found at MM relapse (secondary EM), we found association with high D-S stage, high LDH, high CRP, high Ca, del13q and gain1q. Conclusion EM remains an aggressive disease with poor prognosis regardless of use of novel drugs. Surprisingly, in our group of patients, most EM disease developed early in the course of the disease - more than 60% at first relapse. We analyzed risk factors connected to development of EM and found that LDH, hemoglobin, thrombocytes and M-Ig status were associated with EM development. We suggest that in such patients, PET/CT or whole body MRI should be performed regularly to ensure early detection of EM. Grant support: AZV 17-29343A. Disclosures Maisnar: BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

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VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽

10.1182/blood-2019-124403 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1835-1835 ◽

Cited By ~ 4

Author(s):

Katrina M Piedra ◽

Hani Hassoun ◽

Larry W. Buie ◽

Sean M. Devlin ◽

Jessica Flynn ◽

...

Keyword(s):

Multiple Myeloma ◽

Venous Thromboembolism ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cancer Trial ◽

Oncology Research ◽

Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

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Beta-Blockers Improved Survival Outcomes in Patients with Multiple Myeloma: A Retrospective Evaluation

Blood ◽

10.1182/blood.v128.22.3306.3306 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3306-3306

Author(s):

Yi L. Hwa ◽

Qian Shi ◽

Shaji Kumar ◽

Martha Q. Lacy ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Mayo Clinic ◽

Cumulative Incidence ◽

Research Funding ◽

Beta Blockers ◽

Multivariable Analysis ◽

Advisory Committees ◽

Risk Of Death ◽

Cardiac Medication

Abstract Introduction: A recent study revealed an antiproliferative and apoptotic effect of propranolol on multiple myeloma (MM) cells. Our previous small matched case-control study showed longer survival in patients with propranolol and other beta-blockers (BB) intake than those without. This larger scale study was conducted to confirm the positive association of BB and MM survival. Methods: We identified 1971 newly diagnosed pts seen at Mayo Clinic between 1995 and 2010. Cardiac medication usage after diagnosis of MM was extracted from patient records and categorized based on BB intake. Cause of death was collected with death due to MM as the primary interest event and death due to cardiac disease or other reasons as competing risk events. The primary outcomes were MM disease-specific survival (DSS) and overall survival (OS). Cumulative incidence functions and Kaplan-Meier method were used to estimate the 5-year cumulative incidence rate (CIR) of MM death and OS rate, respectively. DSS and OS were compared by Gray's test and log-rank test, respectively. Multivarable Cox proportional hazard models were used to estimate the adjusted cause-specific HR (HRCSadj.) and hazard ratio (HRadj.) for DSS and OS, respectively, adjusting for demographics, disease characteristics, diagnosis year, and various chemotherapies. Results: 930 (47.2%) of MM patients had no intake of any cardiac medications; 260 (13.2%) had BB only; 343 (17.4%) used both BB / non-BB cardiac medications; and 438 patients (22.2%) had non-BB cardiac drugs. Five-year CIR of MM death and OS rate were shown in table. Superior MM DSS was observed for BB only users, compared to patients without any cardiac drugs (HRCSadj., .53, 95% confidence interval [CI], .42-.67, padj.<.0001) and non-BB cardiac drugs users (HRCSadj., .49, 95% CI, .38-.63, padj.<.0001). Patients received both BB and other cardiac drugs also showed superior MM DSS than non-cardiac drugs users (HRCSadj.., .54, 95% CI, .44-.67, padj.<.0001) and non-BB cardiac drug users. (HRCSadj., .50, 95% CI, .40-.62, padj.<.0001). MM DSS does not differ between BB users with and without other cardiac drugs (padj.=0.90). Multivariable analysis showed the same pattern for OS. None of the MM therapies impacted the differences in DSS and OS among BB intake groups (interaction padj.>.60). Conclusion: MM patients with BB intake showed reduced risk of death due to MM and overall mortality compared to patients who used non-BB cardiac or never used cardiac drugs. The result warrants further investigation for anti-cancer effect of BB in MM. Disclosures Shi: Mayo Clinic: Employment. Kumar:Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy. Gertz:NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; Annexon Biosciences: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:pfizer: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Jannsen: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Risk Factors Associated with the Development of Infusion-Related Reactions in Patients with Chronic Lymphocytic Leukaemia Treated with Anti-CD20 Monoclonal Antibodies: Analysis of the CLL11 Study Dataset

Blood ◽

10.1182/blood.v124.21.3339.3339 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3339-3339 ◽

Cited By ~ 4

Author(s):

Ciara Louise Freeman ◽

Mark Dixon ◽

Richard Houghton ◽

Kathryn Humphrey ◽

Gunter Fingerle-Rowson ◽

...

Keyword(s):

Risk Factors ◽

Monoclonal Antibodies ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukaemia ◽

Signs And Symptoms ◽

Leukemic Cells ◽

Tumour Burden ◽

Advisory Committees ◽

Anti Cd20

Abstract Background: The administration of anti-CD20 monoclonal antibodies (mAb) in patients with B-cell lympho-proliferative disorders is frequently accompanied by a constellation of signs and symptoms that have been labelled as infusion-related reactions (IRR). The pathophysiology of IRR remains poorly understood as do predictors of risk, which may relate to the mechanism of action of the anti-CD20, disease-related factors such as tumour burden or host factors such as polymorphisms of Fc gamma receptor 3A (FcγRIIIA). In the CLL11 trial (NCT01010061), patients with previously untreated chronic lymphocytic leukaemia and comorbidities were randomised to receive either rituximab (type I anti-CD20 mAb) or obinutuzumab (type II and glycoengineered anti-CD20 mAb) in combination with chlorambucil for six cycles. Obinutuzumab led to faster depletion of B cells and achieved an improvement in outcome parameters such as response and progression-free survival compared with the rituximab arm, but was also associated with a higher rate and increased severity of IRR. To better understand the profile of risk for IRR in patients with CLL, we performed an exploratory analysis on data obtained from patients treated with either one of the two antibodies given in combination with chlorambucil. Methods: Patients from the prospective, randomized Phase III CLL11 study who received a first infusion of obinutuzumab (N=331) or rituximab (N=326) were included. Baseline pre-treatment risk factors thought to play a possible role in the development of IRR were identified a priori and included patient demographics, concurrent conditions and premedications, parameters of disease burden, prognostic factors, laboratory variables and FcγR genotype. Baseline values for mean fluorescence intensity (MFI) of CD20, gated on the circulating CLL clone, and MFI of CD16, gated on the natural killer (NK) cell population (CD56+16+) in peripheral blood were also available for N=510 patients. The primary outcome, development of an IRR with the first infusion, was defined as the occurrence of related signs and symptoms during or within 24 hours of administration of antibody. Due to the short-term nature of the initial IRR a multivariate logistical regression analysis was performed rather than a time to event analysis. Internal validation of this model, derived from a single dataset, was conducted using the established resampling technique of bootstrapping. This assessed the proportion of times each variable retained significance at α=0.10 when the model was fitted to bootstrapped samples of the dataset. Results: Patients that appeared to be at greater risk of developing any grade of IRR with the first infusion of rituximab or obinutuzumab were those treated with obinutuzumab, those with higher surface expression CD20 on CLL cells (MFI CD20) and greater FcγRIIIA (MFI CD16) on NK cells in peripheral blood, those with higher affinity FcγRIIIA genotype (VV), more pronounced neutropenia and splenomegaly at baseline (Table 1). Higher baseline absolute lymphocyte count and the presence of respiratory comorbidity also appeared to increase risk. All variables significant for inclusion in the model are shown in Table 1. Looking at those patients treated with obinutuzumab only, the most important determinant of risk was MFI CD20 (OR 3.6 95% CI 1.6-7.9). The impact of glucocorticoid premedication in reducing risk in obinutuzumab treated patients was not sufficient to reach significance, however, patients were not randomised to this intervention. Conclusion: This work identifies novel disease- and patient-specific biological variables that appear to play a role in the development of IRR in patients with CLL treated with anti-CD20 mAb, although the treatment received (obinutuzumab >rituximab) confers greatest risk. In addition to parameters of tumour burden, target antigen expression and gene polymorphisms of FcγR also appear to contribute to the risk of developing an IRR. Our results support the hypothesis that higher rates of IRR seen with the administration of obinutuzumab may result from stronger activation upon binding to CD20 on leukemic cells and subsequent enhanced cross-linking between CD20 expressing leukemic cells and FcγRIIIA bearing effector cells. Further studies involving obinutuzumab in this patient population will be needed to externally validate the results of this exploratory analysis. Disclosures Freeman: Roche Pharmaceuticals: clinical research fellowship supported by Roche Pharmaceuticals (secondment from Bart's) Other. Dixon:Roche Pharmaceuticals: Employment. Houghton:Roche Pharmaceuticals: Employment. Humphrey:Roche: Employment. Fingerle-Rowson:Roche Pharmaceuticals: Employment. Kreuzer:Roche Pharmaceuticals: Research Funding. Engelke:Roche: Travel grants Other. Hallek:Roche Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Goede:Bristol Myers Squibb: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other.

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Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽

10.1182/blood-2021-147829 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3091-3091

Author(s):

Michael Rabaza ◽

Maria Armila Ruiz ◽

Liana Posch ◽

Faiz Ahmed Hussain ◽

Franklin Njoku ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Avascular Necrosis ◽

Sickle Cell ◽

Research Funding ◽

Medical Attention ◽

Cell Disease ◽

Advisory Committees ◽

Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Results of a Phase I Study of Pnk-007, Allogeneic, Off the Shelf NK Cell, Post Autologous Transplant in Multiple Myeloma (NCT02955550)

Blood ◽

10.1182/blood-2019-128467 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4451-4451

Author(s):

Sarah A. Holstein ◽

Sarah Cooley ◽

Parameswaran Hari ◽

Sundar Jagannath ◽

Catherine R Balint ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Phase I Study ◽

Nk Cell ◽

Single Infusion ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background: PNK-007 is an allogeneic, off the shelf cell therapy product enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells. PNK-007 cells exhibit cytotoxicity against various cancer cell types, including multiple myeloma (MM), and secrete cytokines during co-culture with cancer cells. This is a Phase I study of single infusion PNK-007 after autologous stem cell transplant (ASCT) in MM. Methods: Placental CD34+ cells were cultivated in the presence of cytokines for 35 days to generate PNK-007 under cGMP standards followed by release testing. HLA matching and KIR mismatching were not used. Four treatment arms were evaluated on patients (pts) following ASCT: 10 million (M) cells/kg Day (D) 14 with or without recombinant human IL-2 (rhIL-2), 30M cells/kg D14 with rhIL-2, or 30M cells/kg D7 with rhIL-2. rhIL-2 was administered subcutaneously at 6M units every other day for up to 6 doses to facilitate PNK-007 expansion. Pts received variable pre-ASCT induction therapy. Maintenance therapy was permitted after the Day 90-100 visit (D90). Subjects were followed for up to 1-year. Results: 15 pts who received PNK-007 (12 of whom received rhIL-2) were followed on this study. Pts aged 44-69 yrs included 12 newly diagnosed (ND)MM and 3 relapsed/refractory (RR)MM. The 3 RRMM pts had received 1, 2 or 5 prior lines of therapy, with 2 pts having previous ASCT. All pts had been exposed to immunomodulatory drug (IMiDs) and proteasome inhibitors (PIs). No serious adverse events (AEs) were attributable to PNK-007 and no dose-limiting toxicity, GvHD, graft failure or graft rejection were observed. 12/15 pts started maintenance therapy following the transplant while participating in this study, at the physician's discretion. Based on physician assessed responses by International Myeloma Working Group pre-ASCT, of the NDMM pts 10/12 achieved VGPR or better (1 CR and 9 VGPR), 1/12 achieved PR and 1/12 was not assessed during pre-ASCT induction. By D90 10/12 pts achieved VGPR or better (5 CR or sCR and 5 VGPR), 1/12 maintained PR and 1/12 stable disease. At 1-year 9/11 achieved VGPR or better (4 CR or sCR and 5 VGPR), 2/11 were not assessed and 1 was removed from the study prior to 1 year due to failure to respond to ASCT. Of the RRMM pts 2/3 achieved PR and 1/3 was not assessed during pre-ASCT induction, by D90 2/3 achieved VGPR and the pt that had not been assessed pre-ASCT achieved PR. At 1-year, 1 pt maintained VGPR, 1 pt was not assessed and 1 pt did not continue to the 1-year visit. Using a validated Euro-flow minimal residual disease (MRD) assay of bone marrow aspirate (BMA) samples, of the NDMM pts 4/12 were MRD negative (MRD-) pre-ASCT; by D90 9/12 were MRD-. At 1-year 6/12 were MRD-, 2/12 had insufficient BMA to perform testing, 2/12 refused BMA procedure, 1/12 did not convert to MRD-, and 1 was removed from the study prior to 1-year due to failure to respond to ASCT. Of the RRMM pts 0/3 were MRD- pre-ASCT with 1/3 having insufficient BMA to perform testing; by D90 1/3 were MRD-. At 1-year 1/3 was MRD-, 1/3 did not convert to MRD- and 1 pt did not continue to the 1-year visit. PNK-007 infusion did not interfere with immune reconstitution kinetics. Platelet, neutrophil, and absolute lymphocyte counts recovered by day 28 post-ASCT in 12/15 patients. All pts' sera tested negative for the presence of anti-HLA antibodies at all timepoints indicating the absence of humoral immunity and alloantibodies to PNK-007. Conclusion: PNK-007 is the first fully allogeneic, off the shelf CD34+ derived NK cell product in MM clinical trials. A single infusion of PNK-007 up to 30M cells/kg with and without rhIL-2 was well tolerated in the post-ASCT setting. We established the feasibility of infusing PNK-007 as early as 7 days post-ASCT without negative impact on blood count recovery or successful engraftment. BMA MRD- status was observed in 7/9 MRD evaluable pts at 1-year post ASCT. These clinical data are encouraging and warrant further evaluation. Disclosures Holstein: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees. Cooley:Fate Therapeutics, Inc: Employment, Equity Ownership. Hari:Cell Vault: Equity Ownership; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria. Jagannath:BMS: Consultancy; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau. Balint:Celgene: Equity Ownership; Celularity, Inc: Employment. Van Der Touw:Celularity, Inc: Employment. Zhang:Celularity Inc: Employment. Hariri:Celularity Inc: Employment. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding.

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Metaphase Cytogenetics for Risk Stratification in Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-122291 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4396-4396

Author(s):

Patrick Mellors ◽

Moritz Binder ◽

Rhett P. Ketterling ◽

Patricia Griepp ◽

Linda B Baughn ◽

...

Keyword(s):

Multiple Myeloma ◽

Risk Stratification ◽

Board Of Directors ◽

Research Funding ◽

Multivariable Analysis ◽

Risk Modeling ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cytogenetic Abnormalities ◽

Improve Risk Stratification

Introduction: Abnormal metaphase cytogenetics are associated with inferior survival in newly diagnosed multiple myeloma (MM). These abnormalities are only detected in one third of cases due to the low proliferative rate of plasma cells. It is unknown if metaphase cytogenetics improve risk stratification when using contemporary prognostic models such as the revised international staging system (R-ISS), which incorporates interphase fluorescence in situ hybridization (FISH). Aims: The aims of this study were to 1) characterize the association between abnormalities on metaphase cytogenetics and overall survival (OS) in newly diagnosed MM treated with novel agents and 2) evaluate whether the addition of metaphase cytogenetics to R-ISS, age, and plasma cell labeling index (PCLI) improves model discrimination with respect to OS. Methods: We analyzed a retrospective cohort of 483 newly diagnosed MM patients treated with proteasome inhibitors (PI) and/or immunomodulators (IMID) who had metaphase cytogenetics performed prior to initiation of therapy. Abnormal metaphase cytogenetics were defined as MM specific abnormalities, while normal metaphase cytogenetics included constitutional cytogenetic variants, age-related Y chromosome loss, and normal metaphase karyotypes. Multivariable adjusted proportional hazards regression models were fit for the association between known prognostic factors and OS. Covariates associated with inferior OS on multivariable analysis included R-ISS stage, age ≥ 70, PCLI ≥ 2, and abnormal metaphase cytogenetics. We devised a risk scoring system weighted by their respective hazard ratios (R-ISS II +1, R-ISS III + 2, age ≥ 70 +2, PCLI ≥ 2 +1, metaphase cytogenetic abnormalities + 1). Low (LR), intermediate (IR), and high risk (HR) groups were established based on risk scores of 0-1, 2-3, and 4-5 in modeling without metaphase cytogenetics, and scores of 0-1, 2-3, and 4-6 in modeling incorporating metaphase cytogenetics, respectively. Survival estimates were calculated using the Kaplan-Meier method. Survival analysis was stratified by LR, IR, and HR groups in models 1) excluding metaphase cytogenetics 2) including metaphase cytogenetics and 3) including metaphase cytogenetics, with IR stratified by presence and absence of metaphase cytogenetic abnormalities. Survival estimates were compared between groups using the log-rank test. Harrell's C was used to compare the predictive power of risk modeling with and without metaphase cytogenetics. Results: Median age at diagnosis was 66 (31-95), 281 patients (58%) were men, median follow up was 5.5 years (0.04-14.4), and median OS was 6.4 years (95% CI 5.7-6.8). Ninety-seven patients (20%) were R-ISS stage I, 318 (66%) stage II, and 68 (14%) stage III. One-hundred and fourteen patients (24%) had high-risk abnormalities by FISH, and 115 (24%) had abnormal metaphase cytogenetics. Three-hundred and thirteen patients (65%) received an IMID, 119 (25%) a PI, 51 (10%) received IMID and PI, and 137 (28%) underwent upfront autologous hematopoietic stem cell transplantation (ASCT). On multivariable analysis, R-ISS (HR 1.59, 95% CI 1.29-1.97, p < 0.001), age ≥ 70 (HR 2.32, 95% CI 1.83-2.93, p < 0.001), PCLI ≥ 2, (HR 1.52, 95% CI 1.16-2.00, p=0.002) and abnormalities on metaphase cytogenetics (HR 1.35, 95% CI 1.05-1.75, p=0.019) were associated with inferior OS. IR and HR groups experienced significantly worse survival compared to LR groups in models excluding (Figure 1A) and including (Figure 1B) the effect of metaphase cytogenetics (p < 0.001 for all comparisons). However, the inclusion of metaphase cytogenetics did not improve discrimination. Likewise, subgroup analysis of IR patients by the presence or absence of metaphase cytogenetic abnormalities did not improve risk stratification (Figure 1C) (p < 0.001). The addition of metaphase cytogenetics to risk modeling with R-ISS stage, age ≥ 70, and PCLI ≥ 2 did not improve prognostic performance when evaluated by Harrell's C (c=0.636 without cytogenetics, c=0.642 with cytogenetics, absolute difference 0.005, 95% CI 0.002-0.012, p=0.142). Conclusions: Abnormalities on metaphase cytogenetics at diagnosis are associated with inferior OS in MM when accounting for the effects of R-ISS, age, and PCLI. However, the addition of metaphase cytogenetics to prognostic modeling incorporating these covariates did not significantly improve risk stratification. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding. Kapoor:Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

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