Introduction

Isatuximab is a cytolytic monoclonal antibody to CD38 used in the therapy of multiple myeloma in combination with pomalidomide and dexamethasone. The addition of isatuximab to pomalidomide and dexamethasone increases the rate of severe infections and serious adverse events associated with pomalidomide and dexamethasone alone, but does not increase the rate of serum ALT, AST or bilirubin elevations. Since its more widespread clinical use, isatuximab has not been implicated in cases clinically apparent liver injury.

Background

Isatuximab (eye” sa tux’ i mab) is a cytolytic, chimeric monoclonal antibody to CD38, a cell surface antigen expressed on hematopoietic and tumor cells including multiple myeloma cells. Studies in cell culture and animal models demonstrated that isatuximab was cytotoxic to malignant multiple myeloma cells. In clinical trials in patients with advance multiple myeloma refractory to standard therapies, the addition of isatuximab to pomalidomide and dexamethasone increased progression-free survival (11.5 vs 6.5 months). Isatuximab was approved in the United States in 2020 as therapy for adults with progressive multiple myeloma after having received two prior therapies including lenalidomide and a proteasome inhibitor. Subsequently, the indications were expanded to include isatuximab in combination with carfilzomib (a proteasome inhibitor) and dexamethasone in patients with refractory or relapsed multiple myeloma after 3 prior therapies. Isatuximab is available in single dose vials of 100 mg in 5 mL and 500 mg in 25 mL (both 20 mg/mL) for intravenous infusion. The recommended dose is 10 mg per kg body weight once weekly for 4 weeks followed by every 2 weeks in combination with the other antineoplastic agents until disease progression or unacceptable toxicity. Combination isatuximab therapy of multiple myeloma has many adverse events and the serious adverse event rates are higher with the addition of isatuximab to pomalidomide and dexamethasone (85% vs 54%), and are mostly severe infusion reactions or myelosuppression, including neutropenia, anemia, lymphopenia, and thrombocytopenia. Rare but potentially severe adverse events include secondary malignancies, and embryo-fetal toxicity.

Hepatotoxicity

Serum ALT elevations developed in 36% of patients receiving isatuximab based chemotherapy vs 31% with pomalidomide and dexamethasone alone and were above 5 times the upper limit of normal in 4% vs 3%. Bilirubin elevations were also frequent with both arms, 16% vs 12%. But no patient developed what was considered drug induced liver injury, the liver test abnormalities being attributed to comorbidities and the advanced stage of multiple myeloma. Since its approval and more widescale use, there have been no published cases of clinically apparent liver injury attributed to isatuximab therapy, although its total clinical experience with its use has been limited.

Likelihood score: E (unlikely cause of clinically apparent liver injury although a potential cause of reactivation of hepatitis B).

Mechanism of Injury

Isatuximab is a monoclonal antibody and is metabolized intracellularly by proteases to short polypeptides and amino acids, which are unlikely to have intrinsic toxicity or to induce immunologically mediated injury. Because it causes some degree of immune suppression, isatuximab may be capable of causing reactivation of hepatitis B virus. Cases of reactivation of varicella virus infection have been reported.

Outcome and Management

The product label for isatuximab does not recommend monitoring of routine liver tests during therapy, but testing patients before starting therapy is appropriate because of the frequency of comorbidities including liver disease in patients with advanced multiple myeloma. Testing for HBsAg and anti-HBc might also be recommended because of the risk of reactivation. Rise in serum aminotransferase levels during therapy should trigger evaluation for other possible causes. Persistence of unexplained ALT levels above 5 times the ULN or appearance of symptoms of liver injury or jaundice should lead to at least temporary discontinuation and more careful monitoring. Pomalidomide is known to be a rare cause of liver injury, and it might be suspected as the culprit in patients receiving it in combination with isatuximab.

Drug Class: Antineoplastic Agents, Monoclonal Antibodies