Cardiotoxicity risk with bortezomib versus lenalidomide for treatment of multiple myeloma: A propensity matched study of 1,790 patients
Authors: John C. Reneau, Dennis Asante, Holly van Houten, Lindsey R. Sangaralingham, Francis K. Buadi, Amir Lerman, Joerg Herrmann
Journal: American Journal of Hematology (2016)

To the Editor: The treatment and outcomes of multiple myeloma (MM) have changed significantly over the past decade with the introduction of novel agents including immunomodulatory drugs like lenalidomide and proteasome inhibitors like bortezomib 1. In view of these developments, side effects, especially those of profound and enduring impact such as cardiovascular toxicities, have gained increased significance. Lenalidomide has been associated with an increased risk of thromboembolism, angina, atrial fibrillation, and bradycardia 2, whereas the labeling information for bortezomib was updated to include precautions regarding possible heart failure (HF) and QT prolongation, even though "causality has not been established." Indeed, in contrast to post-marking reports, two meta-analyses did not show a statistically significant increase in the rate of all-grade or high-grade cardiotoxicities with the use of bortezomib 3, 4. Given the controversy regarding the risk of cardiotoxicities with bortezomib, we conducted a retrospective, propensity matched analysis of administrative claims data based on the OptumLabs Data Warehouse, which includes inpatient, outpatient, and pharmacy data on over 100 million privately insured and a number of Medicare Advantage enrollees throughout the United States 5. All study data were statistically de-identified and accessed using techniques compliant with the Health Insurance Portability and Accountability Act of 1996 and Institutional Review Board regulations. All adults ≥18 years of age with a diagnosis of MM within 12 months prior to an index chemotherapy claim for either lenalidomide or bortezomib between January 1, 2008 and December 31, 2014 were eligible; dexamethasone was part of both regimens. Additional inclusion criteria included a clean period (no lenalidomide or bortezomib) of 12 months before the index chemotherapy and continuous medical and pharmacy enrollment for at least 12 months prior to first chemotherapy administration. Patients receiving other chemotherapy (thalidomide, carfilzomib, pomalidomide, and doxorubicin) during the 12 months prior to first lenalidomide or bortezomib administration were excluded. Inpatient and outpatient claims for the 12 months preceding the date of index chemotherapy were reviewed for evidence of coronary artery disease, peripheral vascular disease, diabetes, renal disease, HF, hyperlipidemia, hypertension, myocardial infarction (MI), and arrhythmia using ICD-9 codes in the primary or secondary diagnoses (Supporting Information Table 1). The Charlson/Deyo comorbidity index was used to assess the patient's overall baseline comorbidity burden by using ICD-9 codes to identify the 17 conditions during the baseline period. The outcome measures were (1) hospitalization with primary discharge diagnosis of HF, MI, or arrhythmia and (2) inpatient or outpatient procedures of percutaneous coronary intervention (PCI), coronary artery bypass (CABG), pacemaker (PM) implantation, and automatic implantable cardioverter defibrillator (AICD) implantation. ICD-9 diagnosis and procedure codes as well as CPT codes used in the analysis are available in Supporting Information Table 1. We used propensity score (PS) matching to adjust for imbalances in the baseline covariates between the lenalidomide and the bortezomib group and performed a one-to-one matched analysis without replacement based on the estimated PS for each patient within each group. Propensity scores were computed by modeling a logistic regression, with the dependent variable as the odds of being treated with bortezomib and the independent variables as age, gender, race, year of drug initiation, history of coronary artery disease, peripheral vascular disease, diabetes, renal disease, HF, hyperlipidemia, hypertension, MI, arrhythmia, and Charlson/Deyo index. To assess the success of the matching procedure, we measured standardized differences (measured in percentage points) in observed covariates between the matched groups. Differences that existed between patients treated with bortezomib and lenalidomide were eliminated after PS matching (<10% denotes balance). Baseline data were presented as frequencies or mean values and outcome data in the form of Kaplan–Meier curves of unadjusted events rates and Cox proportional hazard models with hazard ratios (HR) and 95% confidence intervals (CI) for each outcome. Patients were censored at first event, drug switch (bortezomib, carfilzomib, lenalidomide, and doxorubicin), or end of enrollment. The event rates per 100 patient-years (PY) were computed using the person-year method. SAS software version 9.3 (SAS Institute Inc, Cary, NC) and Stata version 14 were used for analyses. A total of 2,452 unique patients were identified, 895 bortezomib patients and 895 lenalidomide patients after PS matching (Supporting Information Fig. 1 and Supporting Information Table 2). Patients were followed for a median of 1.2 years in the bortezomib group and 1.3 years in the lenalidomide group (interquartile range 0.56–2.29 years and 0.64–2.55, respectively). The median number of refills for lenalidomide was 9 (interquartile range 4–18). The median number of injections of bortezomib was 14 (interquartile range 5–24). Even though higher, there was no significant difference in the rate of hospitalization for HF for patients treated with bortezomib compared with lenalidomide (3.52/100 PY vs. 2.17/100 PY, HR 1.54, 95% CI 0.84–2.82, Fig. 1A). Similar results for risk of HF hospitalization with bortezomib exposure was noted upon further stratification between patients with a prior diagnosis of HF (12.09/100 PY vs. 9.76/100 PY, HR 1.11, 95% CI 0.46–2.70, Fig. 1B) and those without a prior diagnosis of HF (2.31/100 PY vs. 1.22/100 PY, HR 2.00, 95% CI 0.87–4.64, Fig. 1C). Event-free survival from heart failure hospitalization in multiple myeloma patients treated with lenalidomide or bortezomib, all-comers (A), patients with a prior diagnosis of heart failure (B), and patients without a prior diagnosis of heart failure (C) (P = NS for all). There was also no statistically significant difference in the risk of MI in the bortezomib group compared to lenalidomide (Supporting Information Table 3 and Supporting Information Fig. 2A). Similarly, when evaluating for coronary procedures like PCI and CABG there was no significant differences (Supporting Information Table 3 and Supporting Information Fig. 2B). A combined endpoint for MI, PCI, and CABG yielded similar results (Supporting Information Table 3 and Supporting Information Fig. 2C). Finally, there was also no statistically significant difference in the risk of arrhythmia in those exposed to bortezomib (Supporting Information Table 3 and Supporting Information Fig. 3A). Rates of implantation of PM and AICD devices were also not increased (Supporting Information Table 3 and Supporting Information Fig. 3B). A combined endpoint for arrhythmia, PM, and AICD placement also showed no significant increase in risk in the bortezomib group (Supporting Information Table 3 and Supporting Information Fig. 3C). Despite the well-known differences between real world and clinical trial data, the current results are in agreement with previous meta-analyses that have failed to show an association of bortezomib with adverse cardiac events including HF 3, 4. It is of note though that the rates of MI and HF hospitalization in our patient population (Supporting Information Table 3) were higher than those reported elsewhere for the general adult population in the United States (0.816/100 PY and 0.931/100 PY, respectively) as was the incidence of heart failure in our study population (12.7%) compared with the general adult population (2.1%) 6. These data are worth exploring further, defining the burden of cardiovascular diseases in patients with MM at baseline and on therapy. This is particularly pertinent as concerns of cardiovascular toxicity have been raised for the second generation proteasome inhibitor carfilzomib with post-approval data yet to be acquired for ixazomib and more proteasome inhibitors (marizomib, oprozomib, and delanzomib) in various phases of development for a wide array of malignancies 7. As with all retrospective observational cohort studies, the results are subject to selection bias and confounding. PS matching has been used, which generates a homogenous dataset but does reduce the size of the cohort and thus the representation of the MM population as well as the numbers to allow for accurate risk assessment, while still not being able to account for all possible covariates that could contribute to adverse cardiac outcomes. Also, individual patient records were not reviewed for the current study, but rather we rely on billing data submitted by physicians to insurance providers. Finally, we cannot determine whether or not the degree of HF (for example by New York Heart Failure classification) or cardiac function (for example by ejection fraction) may influence outcomes. It is possible that with a larger sample size, those with higher grades of HF or baseline cardiac function impairment the cardiotoxicity risk could be significantly higher with bortezomib. Finally, our study remains limited by the lack of data on mortality, which limits the ability to define the impact of cardiac events on the survival outcomes of these patients. All this being taken into consideration, the current study indicates that MM patients undergoing therapy with bortezomib as compared with lenalidomide do not face a risk of cardiotoxicity that is statistically higher even though it is numerically higher, also in comparison with the general population. Accordingly, vigilance for cardiotoxicity in patients on bortezomib is advised as it is for MM patients in general. The authors would like to thank OptumLabs for access to the Data Warehouse. The Joerg Herrmann was supported by NIH grant HL 116952. JR and JH designed the study; DA and HVH abstracted data; DA, HVH, and LS analyzed the data; JR wrote the first draft of the manuscript; and JR, DA, HVH, LS, FB, AL and JH edited the manuscript. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. John C. Reneau,1 Dennis Asante,2 Holly Van Houten,3,4 Lindsey R. Sangaralingham,3 Francis K. Buadi,5 Amir Lerman,6 and Joerg Herrmann6* 1Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota; 2Department of Health Sciences Research, Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota; 3Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota; 4OptumLabs, Cambridge, Massachusetts; 5Division of Hematology, Mayo Clinic, Rochester, Minnesota; 6Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota Additional Supporting Information may be found in the online version of this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.