LENALIDOMIDE - TOXICITY

 

Myelosuppression

Lenalidomide-induced myelosuppression is associated with renal dysfunction: adverse events evaluation of treatment-naïve patients undergoing front-line lenalidomide and dexamethasone therapy.
Br J Haematol. 2007 Sep;138(5):640-3.
Niesvizky R, Naib T, Christos PJ, Jayabalan D, Furst JR, Jalbrzikowski J, Zafar F, Mark T, Lent R, Pearse RN, Ely S, Leonard JP, Mazumdar M, Chen-Kiang S, Coleman M.

A case of severe aplastic anemia secondary to treatment with lenalidomide for multiple myeloma.
Eur J Haematol. 2009 Mar;82(3):231-4.
Dasanu CA, Alexandrescu DT.
This is a case report of a 64-year-old male patient who developed progressive pancytopenia three weeks after starting lenalidomide for relapsed MM. A bone marrow biopsy confirmed the diagnosis of severe aplastic anemia. After lenalidomide discontinuation, normal hematopoiesis gradually recovered.

 

Skin rash

Successful desensitization in a patient with lenalidomide hypersensitivity.
Am J Hematol. 2007 Nov;82(11):1030.
Phillips J, Kujawa J, Davis-Lorton M, Hindenburg A.

Lenalidomide desensitization for delayed hypersensitivity reactions in 5 patients with multiple myeloma.
Br J Haematol. 2014 Oct;167(1):127-31.
Lee MJ, Wickner P, Fanning L, Schlossman R, Richardson P, Laubach J, Castells M.
Lenalidomide-associated rash occurs on approximately 27% of patients, and it is severe in 4-5% of cases. Other publications have shown desensitizations protocols for immediate hypersensitivity reactions, but this one illustrates 5 cases with delayed hypersensitivity reactions. The authors propose an interesting protocol that successfully accomplishes a slow desensitization in an outpatient basis over 6 weeks. For example: lenalidomide 2.5 mg x 1 for 1 week, 2.5 mg every 3 days x 3, 2.5 mg every 2 days x 3, 2.5 mg every day x 3, 2.5 mg alternating with 5 mg every day x 6, 5 mg every day x 6, 5 mg alternating with 10 mg every day x 6, and finally 10 mg  every day. 

Outcomes and management of lenalidomide-associated rash in patients with multiple myeloma.
Leuk Lymphoma. 2016 Nov;57(11):2510-5.
Barley K, He W, Agarwal S, Jagannath S, Chari A.

 

Diarrhea

Lenalidomide-induced diarrhea in patients with myeloma is caused by bile acid malabsorption that responds to treatment.
Blood. 2014 Oct 9;124(15):2467-8.
Pawlyn C, Khan MS, Muls A, Sriskandarajah P, Kaiser MF, Davies FE, Morgan GJ, Andreyev HJ.
The authors evaluated 12 patients with myeloma who experienced significant diarrhea after therapy with lenalidomide. After testing with selenium homocholic acid taurine scanning, they believed the pathogenesis of the diarrhea was related to bile acid malabsorption. They treated patients with low-fat diet (20% or less of total calories) and a bile acid sequestrant (colesevelam 625 mg x6/day, with food and >4 hours after lenalidomide and other oral drugs). Diarrhea improved in all patients, and it resolved in 50% of them.

 

Thromboembolism

Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma.
Leuk Lymphoma. 2007 Dec;48(12):2330-7.
Niesvizky R, Martínez-Baños D, Jalbrzikowski J, Christos P, Furst J, De Sancho M, Mark T, Pearse R, Mazumdar M, Zafar F, Pekle K, Leonard J, Jayabalan D, Coleman M.
In this study, the prophylactic use of low-dose aspirin (81 mg) was effective in preventing an increased incidence of venous thromboembolism in patients with multiple myeloma treated with thalidomide or lenalidomide.

Thromboembolic events with lenalidomide-based therapy for multiple myeloma.
Cancer. 2008 Apr 1;112(7):1522-8.
Menon SP, Rajkumar SV, Lacy M, Falco P, Palumbo A.
This is a report of 125 myeloma patients enrolled in 3 clinical trials involving treatment with lenalidomide. 10 patients (8%) developed DVT, including 4 patients who did not receive prophylaxis. DVT was observed in 6 of 104 patients who received aspirin prophylaxis (6%). No difference in the rate of DVT was observed between patients who received erythropoietin and those who did not, whereas there was a trend for higher rate of DVT in patients treated with high-dose dexamethasone compared with low-dose corticosteroids (either prednisone, or dexamethasone 40 mg/month), but the difference was not statistically significant.

Survival effect of venous thromboembolism in patients with multiple myeloma treated with lenalidomide and high-dose dexamethasone.
J Clin Oncol. 2010 Jan 1;28(1):132-5.
Zangari M, Tricot G, Polavaram L, Zhan F, Finlayson A, Knight R, Fu T, Weber D, Dimopoulos MA, Niesvizky R, Fink L.
In this retrospective analysis of 353 patients treated with lenalidomide and high-dose dexamethasone, VTE occurred in 17% of patients.

Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide.
Blood. 2012 Jan 26;119(4):933-9.
Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A.
342 patients with newly diagnosed multiple myeloma were treated with lenalidomide and randomized to either aspirin 100 mg PO daily or enoxaparin 100 mg SC daily. Results:
  - Venous thromboembolism developed in 2.3% of patients in the aspirin group, and 1.2% in the enoxaparin group
  - Pulmonary embolism developed in 1.7% of patients in the aspirin group, and 0% in the enoxaparin group
  - No cases of arterial embolism were observed
The authors concluded that aspirin is sufficient in the prophylaxis of venous thromboembolism for patients receiving lenalidomide.

Silent venous thromboembolism in multiple myeloma patients treated with lenalidomide.
Int J Hematol. 2015 Sep;102(3):271-7.
Isoda A, Sato N, Miyazawa Y, Matsumoto Y, Koumoto M, Ookawa M, Sawamura M, Matsumoto M.
In this study of 80 patients with relapsed/refractory myeloma, treatment with lenalidomide was associated with 18% rate of asymptomatic venous thromboembolism (VTE) of the lower extremities, despite prophylaxis with aspirin 100 mg daily. Patient were monitored with plasma D-dimer levels. VTE developed at a median time of 3 months after initiation of the lenalidomide therapy (range, 1-13 months).

 

 


Giampaolo Talamo, MD