Lenalidomide Treatment in Patients with Renal Insufficiency: More Neutropenia Observed

Abstract & Commentary

By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: Neutropenia occurs commonly in lenalidomide treated multiple myeloma patients. In this review of a series of newly diagnosed patients, pre-treatment renal dysfunction was clearly associated with increased dose modification-requiring neutropenia.

Source: Niesvizky R, et al. Br. J. Haematol. 2007;138:640-643.

The introduction of lenalidomide represents a considered advance in the management of multiple myeloma. An analog of thalidomide, lenalidomide (Revlimid®) has been promoted because it is both more potent and better tolerated than the parent compound.1 Its effectiveness was established for the treatment of relapsed or refractory myeloma and it is currently under investigation as a first line approach. Typically, lenalidomide is administered 25 mg, orally, daily, on days 1 through 21 of a 28-day cycle. Dose reductions are called for when grade 3 or 4 neutropenia, thrombocytopenia, or other drug-related toxicity occurs. Lenalidomide is primarily excreted through the kidneys and renal insufficiency may affect the incidence of adverse events. The current analysis was undertaken to determine the relationship between preexisting renal insufficiency and the development of grade 3 or higher myelosuppression during lenalidomide therapy.

For this, Niesvizky and colleagues at Cornell University examined data on 72 patients receiving combination lenalidomide and dexamethasone as part of a phase II protocol for the treatment of newly diagnosed multiple myeloma. Eligible patients had symptomatic, measurable disease and a performance status of > 70% (Karnofsky). All patients received lenalidomide and dexamethasone in the 28-day cycle. Dexamethasone 40 mg was given orally once a week. Lenalidomide 25 mg was given orally on days 1 through 21. Concurrent medications included aspirin 82 mg daily, omeprazole 20 mg daily, and trimethoprim/sulfamethoxazole three days per week. Of the 72 patients enrolled, 14 had a baseline creatinine clearance of < 0.67 mL/sec (< 40 mL/min).

For grade 3 neutropenia, there were 3 successive dose reductions: level 1; lenalidomide maintained at 25 mg per day but patients treated with granulocyte colony-stimulating factor (G-CSF); level 2; lenalidomide dose reduced to 15 mg per day; level 3, lenalidomide reduced to 10 mg per day; and, level 4; lenalidomide given at 5 mg per day.

Of the 72 patients in the study, 14 developed myelosuppression requiring dose reduction to at least level 1. Of these 14 patients, eight required further reduction to level 2, four patients were reduced to level 3, and one patient to level 4. With regard to renal function, 8 of the 14 requiring dose adjustments had a baseline creatinine clearances of less than 40 mL/min.

Thus, the baseline creatinine clearance of less than 40 mL/min was associated with grade 3 or higher myelosuppression and a need to reduce lenalidomide dosing. The median dose reduction-free survival time for patients with a creatinine clearance of less than 40 mL/min was 6.2 months (95% confidence interval [CI] 1.8 to 8.5 months).

When stratified by baseline creatinine clearance using the 58 patients with a creatinine clearance of greater than 40 mL/min as the reference group, the Kaplan-Meier log-rank test yielded a P value of less than 0.0001. The associated hazard rate was 8.4 (95% CI 2.9 to 24.7, P=0.0001) for patients with a creatinine clearance of less than 40 mL/min vs greater than 40 mL/min, indicating an 8.4-fold increased likelihood of lenalidomide dose reduction for these patients.

COMMENTARY

In this analysis of 72 patients treated at a single institution, baseline renal function as estimated by creatinine clearance, predicted both the development of myelosuppression and the need for lenalidomide dose reduction. Other groups reported at last year's American Society of Hematology annual meeting that pretreatment renal insufficiency was associated with lenalidomide-induced thrombocytopenia and platelet transfusion requirements.2,3

These findings indicate that special caution must be exercised for those myeloma patients with compromised renal function with regard to lenalidomide treatment. Renal function should be estimated prior to treatment and consideration given to initial lenalidomide dose reductions in an effort to reduce the incidence of severe neutropenia. Additional studies are called for examining the pharmacokinetics, safety and efficacy of lenalidomide in multiple myeloma patients who are to be treated with this regimen.

References

1. Anderson KC. Semin Hematol. 2005;42(4 Suppl 4):S3-8.

2. Reece DM, et al. Blood. 2006;108:1013a.

3. Weber D, et al. Blood. 2006;108:1012a.