Lenalidomide is an immunomodulatory and antineoplastic agent that is used in the therapy of multiple myeloma. Lenalidomide is associated with a low rate of serum aminotransferase elevations during therapy and has been implicated in causing rare instances of clinically apparent liver injury which can be severe.


Lenalidomide (len" a lid' oh mide) is a thalidomide derivative that has similar but more potent activity as an antineoplastic agent. Thalidomide and its derivatives have immunomodulatory, antiinflammatory antiangiogenic and antineoplastic activities. The mechanism of action of these agents in the treatment of multiple myeloma is not well defined but may relate to inhibition of tumor necrosis factor (TNF) alpha, a potent proinflammatory cytokine or to stimulation of T and NK cell activity. The thalidomide derivatives have direct cytotoxic effects against myeloma cells in culture and have potent antiangiogenic activities. Lenalidomide was approved for use in multiple myeloma in 2005 and was subsequently approved for use in myelodysplastic syndromes and mantle cell lymphoma. Lenalidomide is available in capsules of 2.5, 5, 10, 15, 20 and 25 mg under the brand name Revlimid. The recommended doses vary by indication and, like thalidomide, its use is restricted because of proven teratogenicity. Side effects of lenalidomide are common and include sedation, dizziness, orthostatic hypotension, neutropenia, lymphopenia, peripheral neuropathy, and arterial and venous thromboembolism (for which reason it is often given with anticoagulation). Rare but potentially severe adverse events include severe cutaneous reactions, seizures, tumor lysis syndrome and hypersensitivity reactions. Lenalidomide is a teratogen and possible cause of severe birth defects and is available only as a part of a strict Risk Evaluation and Mitigation Strategy (REMS), which requires physician training, written patient informed consent, strict birth control measures, regular monitoring and reporting.


Serum enzyme elevations occur in 8% to 15% of patients taking lenalidomide and are more frequent with higher doses. The enzyme abnormalities are usually mild and self-limited, and only rarely require drug discontinuation. In addition, lenalidomide has been implicated in rare instances of clinically apparent, acute liver injury which can be severe and has led to deaths from acute liver failure. The onset of injury is typically within 1 to 8 weeks of starting therapy. The pattern of serum enzyme elevation at the time of presentation can be either hepatocellular or cholestatic; however, the injury tends to be cholestatic and can be prolonged. Immunoallergic and autoimmune features are not common. Several instances of acute liver injury associated with lenalidomide therapy have occurred in patients with other apparent causes of liver disease or with preexisting chronic hepatitis B or C. If performed during the acute injury, liver biopsy shows hepatocellular necrosis and inflammatory cell infiltration, consistent with acute drug induced injury. In some instances there is bile duct injury and loss resulting in progressive cholestatic liver injury suggestive of vanishing bile duct syndrome. Lenalidomide has also been shown to increase indirect bilirubin levels in patients with underlying Gilbert syndrome, causing a mild hyperbilirubinemia during therapy that soon resolves with stopping treatment and is otherwise benign.

Thalidomide and its derivatives have also been implicated in causing an increased risk of graft-vs-host disease after autologous or allogeneic hematopoietic stem cell transplantation (HSCT) as well as after liver, kidney and heart transplantation. There appears to be cross reactivity to this complication among lenalidomide, pomalidomide and thalidomide. Therapy usually requires discontinuation of the antineoplastic agent as well as treatment with high doses of corticosteroids and tacrolimus or sirolimus. Furthermore, hepatic graft-vs-host disease can occasionally present with an acute hepatitis that resembles hepatocellular drug induced liver injury.

Reactivation of hepatitis B has been reported in patients receiving thalidomide, lenalidomide and pomalidomide, but generally only after HSCT and the role of these agents in causing reactivation is not always clear. Indeed, in studies of large numbers of patients treated for multiple myeloma, the major risk factor for reactivation was found to be HSCT rather than the specific antineoplastic drugs being used. Indeed, lenalidomide therapy is associated with a reduced risk of reactivation in patients with HSCT (although dexamethasone, thalidomide and bortezomib were not), perhaps because of the immune enhancement typically caused by lenalidomide.

Likelihood score: C (probable rare cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of lenalidomide hepatotoxicity is not clear, but it may be related to its activity in reducing TNF-α production, a potent inflammatory cytokine that activates T cells and promotes inflammation, but is also necessary for normal liver regeneration. Several of the reported cases of hepatotoxicity have occurred in patients with underlying chronic liver disease (hepatitis B, C or nonalcoholic fatty liver), and another possibility is that lenalidomide may worsen preexisting hepatic conditions.

Outcome and Management

The severity of lenalidomide induced liver injury ranges from transient, asymptomatic elevations in serum enzymes to acute liver injury with jaundice to severe acute liver failure and death. The liver injury usually starts to resolve within a week of stopping the medication, but prolonged jaundice with bile duct injury and possible vanishing bile duct syndrome have also been reported. Rechallenge should be reserved for cases of mild liver injury in which the agent is considered very necessary and done with caution and careful monitoring. Nevertheless, instances of reinitiation of therapy without subsequent recurrence of liver injury have been reported.

Drug Class: Antineoplastic Agents, Miscellaneous

Other Related Drugs: Pomalidomide, Thalidomide


Case 1. Acute liver injury during lenalidomide therapy of multiple myeloma.(1)

A 50 year old man with refractory and relapsed multiple myeloma was started on a course of lenalidomide after multiple cycles of chemotherapy and both autologous and allogeneic hematopoietic stem cell transplants that provided only temporary remissions. Ten days after starting lenalidomide [10 mg daily], he was found to have abnormal liver tests with a serum ALT of 505 U/L, AST 246 U/L, Alk P 198 U/L, but bilirubin and INR normal. Serum enzyme levels had been normal before starting lenalidomide. He did not drink alcohol and had no risk factors for viral hepatitis. Of note, 3 years earlier he had developed angioedema and a severe skin rash without liver test abnormalities after three months of cyclic lenalidomide therapy. In the interim he had undergone an allogeneic HSCT.

Lenalidomide was discontinued and he was admitted for evaluation and liver biopsy. Blood counts demonstrated eosinophilia (1344/µL). Tests for hepatitis A, B, C and E as well as CMV, EBV, HIV and herpes simplex and zoster infection were negative. Ultrasound showed normal appearing liver without evidence of biliary obstruction. Liver biopsy showed prominent portal and lobular inflammation with a mixed cellular infiltrate rich in eosinophils, lobular areas with confluent necrosis and mild endothelitis and occasional biliary cell injury in portal areas. The liver histology was considered consistent with an acute drug induced hepatitis superimposed upon mild graft-vs-host disease. In further follow up, liver tests improved and were normal 6 weeks later (Table).

Key Points

Laboratory Values


This man developed asymptomatic and anicteric hepatitis within 10 days of starting lenalidomide. Typical of lenalidomide hepatotoxicity was the rapid latency to onset (less than one month), the hepatocellular pattern of injury, and the rapid improvement with stopping the medication. Also typical was the previous history of autologous or allogeneic HSCT. Indeed, one possibility is that this represented the worsening of an underlying graft-vs-host disease by lenalidomide therapy, an indirect form of drug induced liver injury. In preparation of use of lenalidomide to treat multiple myeloma, maintenance immunosuppressive therapy for prevention of graft-vs-host disease is typically withdrawn. In this case, it was unclear whether maintenance immunosuppression was continued.



Lenalidomide – Revlimid®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



Zanella MC, Rubbia-Brandt L, Giostra E, Chalandon Y, Hadengue A, Spahr L. A case of drug-induced hepatitis due to lenalidomide. Case Rep Gastroenterol. 2011;5:217–22. [PMC free article: PMC3088752] [PubMed: 21552449]


References updated: 30 August 2022

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