Toward Therapeutic Drug Monitoring of Lenalidomide in Hematological Malignancy? Results of an Observational Study of the Exposure-Safety Relationship

Zaiwei Song; Lan Ma; Li Bao; Yi Ma; Ping Yang; Dan Jiang; Aijun Liu; Lu Zhang; Yan Li; Yinchu Cheng; Fei Dong; Rongsheng Zhao; Hongmei Jing

doi:10.3389/fphar.2022.931495

Toward Therapeutic Drug Monitoring of Lenalidomide in Hematological Malignancy? Results of an Observational Study of the Exposure-Safety Relationship

Front Pharmacol. 2022 Jun 23:13:931495. doi: 10.3389/fphar.2022.931495. eCollection 2022.

Authors

Zaiwei Song^{1

2}, Lan Ma³, Li Bao⁴, Yi Ma^{1

2}, Ping Yang^{1

2}, Dan Jiang^{1

2}, Aijun Liu⁵, Lu Zhang⁶, Yan Li³, Yinchu Cheng^{1

2}, Fei Dong³, Rongsheng Zhao^{1

2}, Hongmei Jing³

Affiliations

¹ Department of Pharmacy, Peking University Third Hospital, Beijing, China.
² Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China.
³ Department of Hematology, Peking University Third Hospital, Beijing, China.
⁴ Department of Hematology, Beijing Jishuitan Hospital, Beijing, China.
⁵ Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
⁶ Department of Hematology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Abstract

Objective: Continuous lenalidomide (LEN) therapy is important to achieve a therapeutic effect in patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). However, despite dose adjustment according to kidney function, many patients discontinue LEN therapy because of hematological toxicity. To date, therapeutic drug monitoring (TDM) of LEN has not been performed in oncology, and no target concentration level has been yet defined. The aim of this study was to evaluate the exposure-safety relationship of LEN and determine the target concentration for toxicity. Materials and Methods: A prospective observational study was designed and implemented. Blood samples were collected at 0.5 h (trough concentration, C_min) before oral administration and 1 h (C_1h) thereafter on the day. Clinical data were gathered from patients' medical records and laboratory reports. Outcome measures of hematological toxicity were defined by the Common Terminology Criteria for Adverse Events. The concentration values were dichotomized by receiver operating characteristic (ROC) curve analysis, and the association between exposure and outcome was determined using the logistic regression model. Results: Out of the 61 patients enrolled in this study, 40 (65.57%) had MM, and 21 (34.43%) had NHL. Hematological toxicity was reported in 15 (24.59%) patients. The LEN C_min showed remarkable differences (p = 0.031) among patients with or without hematological toxicity, while no association between C_1h values and toxicity was noted (p>0.05). By ROC analysis, a C_min threshold of 10.95 ng/mL was associated with the best sensitivity/specificity for toxicity events (AUC = 0.687; sensitivity = 0.40; specificity = 0.935). By multivariate logistic regression, an LEN C_min below 10.95 ng/mL was associated with a markedly decreased risk of hematological toxicity (<10.95 ng/mL vs. >10.95 ng/mL: OR = 0.023, 95% CI = 0.002-0.269; p = 0.003). Conclusions: We demonstrate that the LEN trough concentration correlates with hematological toxicity, and the C_min threshold for hematological toxicity (10.95 ng/mL) is proposed. Altogether, LEN TDM appears to be a new approach to improve medication safety and achieve continuous treatment for patients with NHL or MM in routine clinical care.

Keywords: hematological malignancies; hematological toxicity; lenalidomide; therapeutic drug monitoring; trough concentration.