Spectrum of Cerebrovascular Disease in Multiple Myeloma Patients Undergoing Chemotherapy
Authors: Hinduja Archana , Limaye Kaustubh , Ravilla Rahul , Sasapu Appalanaidu , Papanikolaou Xenofon , Waheed Sarah 
Published: October 2019

Abstract
Introduction: The objective of study was to determine the risk factors, stroke mechanisms and outcome following a stroke in Multiple myeloma (MM) patients.
Materials and Methods: We conducted a matched cohort study from a prospective database of MM patients enrolled in TT2, TT3A, TT3B protocols who developed a vascular event (transient ischemic attack, ischemic stroke and intracerebral hemorrhage) from 1998 to 2014 with age, sex and treatment matched controls. Comparison of baseline demographics, risk factors, myeloma characteristics, laboratory values and mortality between both groups was performed using Pearson's Chi-square test for categorical variables and student T test for continuous variables. Multivariate logistic regression analysis was performed to identify risk factors associated with stroke. For statistical analysis SAS 9.4 software was used and p value of ≤ 0.05 was considered significant. Strokes were classified using the modified Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria.
Results: Of 1148 patients, 46 developed a vascular event (Ischemic stroke (TIA)-33, Transient ischemic attack-11, Hypertensive intracerebral hemorrhage-2). On univariate analysis, predictors of stroke were a positive smoking history (26.1% vs 13% p=0.0381), renal insufficiency (23.9% vs 8.0% p=0.0039), hemodialysis (10.9 vs 0.7% p=0.004) and MM Stage I and II as opposed to Stage III (Stage I - 23.9% vs 9.4%, Stage II - 17.4% vs 12.3, Stage III - 58.7% vs 78.3% p=0.025). Despite the lack of significant difference in the baseline laboratory values between both groups, among the cases, there was a significant decrease in the platelet count (112.6 vs 255.2, p<0.0001) and elevation in INR (1.25 vs 1.08, p=0.0096) during the vascular insult when compared to their baseline values.
On multivariate analysis, independent predictors of stroke were renal insufficiency (Odds Ratio, 3.528, 95% CI, 1.36-9.14; p=0.0094) and MM Stage I and II (Odds Ratio, 2.770, 95% CI, 1.31-5.81; p=0.0073). The ischemic strokes subtypes were: Large vessel disease 6%, cardioembolic 18%, small vessel disease 21%, other known etiologies 49% (hypercoaguable state; watershed; others) and cryptogenic in 6%. Following ischemic event, antiplatelet agents were used in 16 patients, anticoagulation in 7 patients but 23 patients were ineligible for both due to thrombocytopenia. In our cohort, 78% were discharged home or rehabilitation facility, 4% were transferred to long-term nursing facility and in hospital mortality was 15%.
Conclusion: In MMpatient'srenal insufficiency andMM Stage I and II were associated with increased stroke risk. Besides hypercoagulability other mechanisms like atrial fibrillation, watershed strokes and small vessel disease played major role. Table 1.Demographic and disease characteristics of multiple myeloma patients experiencing a stroke compared to controlsVariableStroke (N=46)No Stroke (N=138)p-valueAge [mean (sd)]60.6 (7.7)60.7 (7.8)0.8960Female50.0 (23)41.6 (57)0.3023Race Caucasian95.7 (44)90.6 (125)0.3635#Hypertension54.4 (25)43.5 (60)0.2003HPL33.3 (15/45)26.1 (36)0.3464Diabetes17.4 (8)9.4 (13)0.1409CAD10.9 (5)10.9 (15)>0.99CHF4.4 (2)8.7 (12)0.5237AFIB17.4 (8)9.4 (13)0.1409Smoking26.1 (12)13.0 (18)0.0381ETOH2.2 (1)1.5 (2)>0.99Malignancy8.7 (4)16.1 (22/137)0.2159Nephropathy23.9 (11)8.0 (11)0.0039Hemodialysis10.9 (5)0.7 (1)0.0040Protocol TT2 TT3A TT3B54.4 (25) 32.6 (15) 13.0 (6)57.2 (79) 21.0 (29) 21.7 (30)0.3036MM Stage I II III23.9 (11) 17.4 (8) 58.7 (27)9.4 (13) 12.3 (17) 78.3 (108)0.0182MM Isotype IgG IgA FLC-κ FLC-λ Other58.7 (27) 21.7 (10) 8.7 (4) 10.9 (5) 049.3 (68) 24.6 (34) 10.1 (14) 10.9 (15) 5.1 (7)0.6128MM Risk [mean (sd)] Death-0.13 (0.61; N=37) 65.2(30)0.09 (0.67; N=88) 51.5(71)0.0941 0.19OSA: Obstructive sleep apnea, CAD: coronary artery disease, CHF: Congestive heart failure, AFIB: Atrial fibrillation, HPL hyperlipidemia.
Table 1. Results on multivariable logistic model Variable Odds Ratio 95% CI p-value Nephropathy 3.528 1.36 to 9.14 0.0094 MM Stage I or II 2.770 1.31 to 5.81 0.0073

Disclosures
Hinduja: University of Arkansas for Medical Sciences: Employment. Limaye:University of Arkansas for Medical Sciences: Employment. Ravilla:University of Arkansas for Medical Sciences: Employment. Sasapu:University of Arkansas for Medical Sciences: Employment. Waheed:University of Arkansas for Medical Sciences: Employment.