Introduction

Elotuzumab is a humanized monoclonal antibody to cell surface receptor SLAMF7 which is used in combination with other antineoplastic agents in the therapy of multiple myeloma. Elotuzumab has been implicated in rare instances of transient, marked serum enzyme elevations, but has not been linked to instances of clinically apparent liver injury with jaundice.

Background

Elotuzumab (el" oh tooz' ue mab) is humanized IgG1 monoclonal antibody to the cell surface receptor signaling lymphocyte activation molecule family member 7 (SLAMF7), which is a transmembrane glycoprotein that is frequently overexpressed on multiple myeloma cells and is found normally on natural killer (NK) cells. The monoclonal antibody binds to the cell surface receptor and triggers cell apoptosis of cancer cells and activation of NK cells which may increase its antineoplastic activity. In preregistration trials, the addition of elotuzumab to lenalidomide and dexamethasone led to an increase in overall response rates and prolongation of progression-free survival. Elotuzumab was given accelerated approval for use in the United States in 2015. Current indications are as therapy of refractory multiple myeloma administered in combination with lenalidomide (or bortezomib) and dexamethasone or as monotherapy in patients who have failed at least three previous regimens. Elotuzumab is available as a powder for reconstitution in single use vials of 300 or 400 mg under the brand name Empliciti. The recommended dose is 10 mg/kg intravenously every week for 2 cycles and every 2 weeks thereafter until disease progression or unacceptable toxicities occur. Premedication with dexamethasone, diphenhydramine, ranitidine and acetaminophen is recommended. Side effects are common and can include infusion reactions, fatigue, diarrhea, constipation, anorexia, fever, cough, nasopharyngitis, peripheral neuropathy and pneumonia. Uncommon, but potentially severe adverse reactions include severe infusion reactions, bacterial infections and secondary malignancies.

Hepatotoxicity

In preregistration trials of elotuzumab for multiple myeloma, serum enzyme elevations were frequent, but were similar in patients receiving lenalidomide and dexamethasone with elotuzumab as in those on lenalidomide and dexamethasone alone, any ALT elevation occurring in 55% vs 51% and ALT elevations above 5 times the upper limit of normal in 4.4% vs 4.1%. The Food and Drug Administration analysis of submitted results described one case of suspected injury due to elotuzumab with jaundice and serum ALT elevations and a liver biopsy demonstrating possible drug induced liver injury. On the basis of this report, the product label for elotuzumab warned of possible rare instances of hepatotoxicity. Since approval and more wide scale use of elotuzumab, there have been no further published reports of its hepatotoxicity.

Likelihood score: D (possible rare cause of clinically apparent liver injury).

Mechanism of Injury

The cause of liver injury during elotuzumab therapy is not known and separation of the possible role of elotuzumab versus lenalidomide or other antineoplastic agents given concurrently is difficult. Nevertheless, the monoclonal antibody may cause liver injury through its indirect effects on inhibition of SLAMF7 signaling in the liver or activation of NK cells.

Outcome and Management

The liver injury attributed to elotuzumab has usually been self-limited and not associated with symptoms or jaundice. Patients who develop persistent serum enzyme elevations above 5 times the upper limit of normal should have therapy withheld until values decline. Patients who develop symptoms of liver injury or jaundice with serum enzyme elevations should have therapy discontinued. There is no information on possible cross sensitivity to the injury among different monoclonal antibodies.

Drug Class: Antineoplastic Agents, Monoclonal Antibodies

Case 1. Acute liver injury arising during elotuzumab, lenalidomide and dexamethasone therapy of multiple myeloma.

[Modified from: FDA analysis]

A 54 year old man with relapsed multiple myeloma, previously treated with bortezomib, melphalan and dexamethasone followed by autologous hemopoietic stem cell transplant, developed jaundice approximately 7 months after enrolling in an experimental trial of elotuzumab combined with lenalidomide and dexamethasone. He had a previous history of nonalcoholic fatty liver disease and pretreatment laboratory tests demonstrated elevations in ALT (134 U/L) and AST (101 U/L), with normal alkaline phosphatase and bilirubin levels (Table). Further elevations in aminotransferases occurred 6 months into therapy which worsened and were associated with jaundice a few weeks later. All therapy was stopped and he underwent evaluation which showed no evidence of infection with hepatitis A, B, C or E, while abdominal imaging showed fatty liver without changes suggestive of biliary obstruction. Serum bilirubin levels rose to 8.1 mg/dL and a liver biopsy showed changes of chronic hepatitis with cirrhosis and decrease in bile ducts. After several weeks, laboratory test results began to improve and returned to close to baseline levels by 6 weeks after onset.