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Teaching Topic Selinexor–Dexamethasone for Refractory Multiple Myeloma ORIGINAL ARTICLE Oral Selinexor–Dexamethasone for Triple-Class Refractory Multiple Myeloma A. Chari and Others    Administration of selinexor (80 mg) with dexamethasone (20 mg) according to two dosing schedules had been evaluated among patients with myeloma refractory to either four or five drugs in Part 1 of the phase 2 STORM (Selinexor Treatment of Refractory Myeloma) study. In that heterogeneous population, 21% of patients had a partial response or better. On the basis of those findings, the activity of selinexor at a dose of 80 mg twice weekly was examined in a more uniform population in the STORM Part 2 study. Clinical Pearls   What is “triple-class refractory myeloma”? Despite the availability of proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies for multiple myeloma, most patients will have a relapse and refractory disease will develop. An increasing number of patients have triple-class refractory myeloma, defined as disease refractory to proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies, with most patients being treated with all five agents currently in use (carfilzomib, bortezomib, lenalidomide, pomalidomide, and daratumumab; i.e., penta-exposed). Overall survival in patients with myeloma refractory to these classes is short.   What is selinexor? Exportin 1 (XPO1) — the sole known nuclear exporter of tumor suppressor proteins, the glucocorticoid receptor, and oncoprotein messenger RNAs (mRNAs) — is overexpressed in myeloma and correlates with increased bone disease and shorter survival. Selinexor, which was recently approved by the Food and Drug Administration, is a potent, oral, selective inhibitor of nuclear export that binds to Cys528 in the cargo-binding pocket of XPO1, forcing the nuclear localization and functional activation of tumor-suppressor proteins, trapping IκBα in the nucleus to suppress nuclear factor κB activity, and preventing oncoprotein mRNA translation. Selective induction of apoptosis in malignant hematologic and solid tumor cells is a result. Preclinical studies have shown that selinexor with or without dexamethasone induces apoptosis in a number of myeloma cell lines and has antitumor activity in animal models. Morning Report Questions Q. What were the results of the STORM Part 2 study regarding the efficacy of selinexor–dexamethasone for refractory multiple myeloma? A. A partial response or better was observed in 26% of patients (95% confidence interval [CI], 19 to 35), including 2 stringent complete responses (in 2% of the patients), 6 very good partial responses (in 5%), and 24 partial responses (in 20%); because the lower boundary of the confidence interval was more than 10%, the trial met its primary end point. The median time to a partial response or better was 4.1 weeks (range, 1 to 14). A minimal response or better was observed in 39% of patients (95% CI, 31 to 49). The median duration of response was 4.4 months (95% CI, 3.7 to 10.8). Among the patients who had a response, efficacy was consistent across subgroups, including patients with high-risk cytogenetic abnormalities (53% of the patients). Q. What were the most common adverse events in the STORM Part 2 study? A. The most common adverse events that emerged during treatment were thrombocytopenia (in 73% of the patients), fatigue (in 73%), nausea (in 72%), and anemia (in 67%). The most common grade 3 or 4 adverse events were thrombocytopenia (in 59% of the patients), anemia (in 44%), hyponatremia (in 22%), and neutropenia (in 21%). Thrombocytopenia, which is due in part to inhibition by selinexor of thrombopoietin signaling in early megakaryopoiesis, was reversible and was managed with dose interruptions and thrombopoietin-receptor agonists.

Teaching Topic Drug Effects on the Thyroid REVIEW ARTICLE Drug Effects on the Thyroid H.B. Burch    There is a growing list of medications known to adversely affect thyroid function or interpretation of the results of standard thyroid laboratory testing. Clinical Pearls   What are some of the drugs that exert suppressive effects on thyrotropin release without appreciably affecting circulating T4 levels? Several categories of drugs exert suppressive effects on thyrotropin release without appreciably affecting circulating T4 levels, including glucocorticoids, dopamine agonists, somatostatin analogues, and metformin. Although thyrotropin suppression in patients receiving these agents is usually metabolically insignificant, a low thyrotropin level with a normal free T4 level may be confused with subclinical hyperthyroidism, prompting unnecessary evaluation or treatment.   What are some of the drugs that lead to increases in thyroxine-binding globulin? Several drugs lead to increases in thyroxine-binding globulin, including oral estrogen and selective estrogen-receptor modulators, methadone, heroin, mitotane, and fluorouracil. Conversely, reductions in this protein occur with the use of androgens, glucocorticoids, and niacin. The most common and clinically relevant changes in thyroxine-binding globulin occur with the use of estrogen-containing drugs in patients receiving thyroid hormone replacement therapy. In such patients, increases in protein binding lead to additional binding of T4, even in the presence of low free T4 levels. Consequently, patients dependent on exogenous thyroid hormone will have an increased dose requirement after the initiation of oral estrogen treatment. Morning Report Questions Q. What are some of the effects of amiodarone on thyroid function and thyroid laboratory testing? A. Amiodarone, a class III antiarrhythmic agent, is 37.3% iodine by weight and undergoes partial deiodination, releasing approximately 7 mg of iodide per 200-mg tablet, which is roughly 45 times the recommended daily intake of 150 μg for men and nonpregnant women. In addition to inducing hypothyroidism in susceptible patients, iodine from amiodarone causes hyperthyroidism in some patients, a disorder known as type 1 amiodarone-induced thyrotoxicosis. In addition to causing true hypothyroidism and thyrotoxicosis, amiodarone leads to predictable changes in thyroid laboratory test results in euthyroid persons. Inhibition of peripheral and central T4-to-T3 conversion by amiodarone and its major active metabolite, desethylamiodarone, leads to reductions in circulating and intrapituitary T3levels, thereby stimulating thyrotropin-releasing hormone and thyrotropin release through an absence of negative feedback. Increases in thyrotropin prompt thyroidal release of T4, which accumulates further because of inhibited conversion to T3. The net effect of these changes is a serum thyrotropin level that is elevated or at the high end of the normal range, high levels of total and free T4, and a T3 level at the low end of the normal range in a euthyroid patient. Q. What adverse effects can immune checkpoint inhibitors have on thyroid function? A. Immune checkpoint inhibitors, including those that inhibit cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) receptor, have a variety of adverse endocrine effects. Hypophysitis occurs more frequently in patients taking CTLA-4 inhibitors, whereas primary thyroid dysfunction is seen more often with PD-1 inhibitors. Primary thyroid dysfunction is noted variably in the literature as affecting approximately 5 to 10% of patients treated with CTLA-4 inhibitors, 10 to 20% of those treated with PD-1 inhibitors, and more than 20% of patients treated with combination therapy. Most patients receiving such therapy for cancer have painless thyroiditis, presenting with transient thyrotoxicosis followed by hypothyroidism. Hypothyroidism ensues 10 to 20 weeks after the initiation of therapy and is often irreversible.