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Activity and safety of lenalidomide and dexamethasone in patients with multiple myeloma requiring dialysis: a Spanish multicenter retrospective study

2010; Wiley; Volume: 85; Issue: 4 Linguagem: Inglês

10.1111/j.1600-0609.2010.01500.x

1600-0609

Javier de la Rubia, Mónica Roig, Ángela Ibáñez, Inmaculada García, J A Esteban Vera, Carlos Aguilar, Raquel Del Campo, Nicolás Gonzalez, Rafael Martínez, Luis Palomera, Isabel Picón, N. Rodríguez, Miguel Á. Sanz,

Peptidase Inhibition and Analysis

To the Editor: Lenalidomide is an immunomodulating agent that has been shown to be a highly active agent in the management of patients with multiple myeloma (MM) (1, 2), but most studies excluded patients with a serum creatinine level >2.5 mg/dL. Experience with lenalidomide (3) in the management of patients with MM and renal impairment is scarce. We present the results of a retrospective study in a group of 15 patients from 11 Spanish centers with MM and severe renal impairment requiring dialysis and receiving lenalidomide-based therapy at the time of study entry. Response criteria were based on the International Myeloma Working Group (IMWG) criteria (4). Patient features at the time of inclusion are summarized in Table 1. Two patients had renal impairment requiring dialysis before myeloma diagnosis. The remaining thirteen patients developed renal failure at diagnosis or during the evolution of the disease, and it was because of MM (six patients), drug-related (two patients), secondary to underlying diabetes (two patients), and secondary to a tumoral lysis syndrome because of bortezomib (one patient). Finally, no data were available in the remaining two patients. Thirteen (86%) patients received lenalidomide at a dose of 15 mg/d, three times a week after dialysis and in combination with dexamethasone (Table 1). Patients received a median of eight cycles (range, 1–28) of lenalidomide treatment. Hematological toxicity was the toxicity more frequently seen and required dose reduction in eight (53%) patients, and granulocyte-colony stimulating factor prophylaxis in seven (47%). Ten patients developed neutropenia (6 grade 3–4), and seven (47%) patients presented thrombocytopenia (1 grade 3). Finally, two (13%) patients presented grade 2 anemia. Six (40%) patients developed seven infectious episodes during the study period, five of them within the first four cycles of therapy. There were four (57%) bacteremias, two (29%) pneumonias, and one (14%) central venous line infection (Table 2). Other non-hematological complications are shown in Table 2. There were no thromboembolic complications. Overall response rate was 60% (nine patients), with four (29%) achieving complete response (CR), one (7%) patient very good partial response, and four (29%) patients partial response. Median time to best response was 4 months. With a median follow-up of 13 months (range 1–28), median progression-free and overall survival was 15 and 20 months, respectively. Among responding patients, median duration of response has not been reached. Seven (47%) patients have died because of disease progression (five patients) and of infectious complications (two patients) and eight (53%) are still alive, seven with continuous lenalidomde treatment and one off therapy because of disease progression. Renal function remained stable in all but one patient who was spared from dialysis after achieving partial response 3 months after starting treatment. Currently, there is no standard treatment for patients with MM and renal failure requiring dialysis. Results with new agents such as thalidomide and bortezomib are disparate. With thalidomide, experience is scarce and has been associated with a high incidence of hyperkaliemia in patients with serum creatinine >3 mg/dL (5, 6). Better results have been reported with bortezomib-based regimens, with a response rate of 75% with 30% of CR + near CR and with a toxicity profile similar to that observed in patients with normal renal function (7). Lenalidomide has been shown to undergo substantial elimination via the kidneys, and recently, encouraging results have been reported in patients with different degrees of renal impairment (3). However, no data in patients with MM and advanced renal failure requiring dialysis are available. Our report is the first one including this high-risk subgroup of patients with MM and show a response rate of 65% with 29% of CR like that seen in patients with normal renal function (1, 2). Importantly, progression-free and overall survival was also similar to that reported in patients without significant renal failure (1, 2). Finally, among responding patients, median duration of response has not been reached, pointing that durability of response is also comparable to those of patients with MM with normal renal function in the relapsed setting (1, 2). In our series, as in other studies including lenalidomide in patients with mild renal impairment (3, 8, 9), neutropenia was the most common side effect observed and 53% of the patients required dose reduction, suggesting that the dose initially administered was probably too high and that lower doses should be required for patients with severely impaired renal function. In this regard, the currently recommended dose of lenalidomide for patients with end-stage renal disease requiring dialysis is 5 mg/d. However, only one patient in our series received this dose. Thus, no conclusions can be drawn about the impact of the new lenalidomide schedule in the rate of hematological toxicity in this subgroup of patients. Severe infections were a major cause of morbidity and mortality in our patients, with six patients developing seven infectious episodes. Infections are a common toxicity in patients receiving lenalidomide-based therapy, a finding that could be explained by the myelosuppression associated with this drug. In this regard, the majority of infections in our series were observed in the earlier cycles of treatment when the risk of hematological toxicity is greater and highlights the need of a close control of these patients, especially in the initial periods of treatment. In conclusion, this is the first report of lenalidomide-based therapy in patients with relapsing and refractory MM requiring dialysis. Our results show that this combination is associated with a high response rate and a long duration of response. Our study also shows that this therapy is associated with an elevated incidence of hematological toxicity and severe infections, particularly during the first cycles of therapy. Finally, the impact of different lenalidomide schedule needs further evaluation.