Data from two randomized pivotal, phase 3 trials evaluating the combination of lenalidomide and dexamethasone in relapsed/refractory multiple myeloma (RRMM) were pooled to characterize the subset of patients who achieved long-term benefit of therapy (progression-free survival ⩾3 years). Patients with long-term benefit of therapy (n=45) had a median duration of treatment of 48.1 months and a response rate of 100%. Humoral improvement (uninvolved immunoglobulin A) was more common in patients with long-term benefit of therapy (79% vs 55% P=0.002). Significant predictors of long-term benefit of therapy in multivariate analysis were age<65 years (P=0.03), β2-microglobulin <2.5 mg/l (P=0.002) and fewer prior therapies (P=0.002). The exposure-adjusted incidence rate (EAIR) of grade 3–4 neutropenia was lower in patients with long-term benefit of therapy (13.9 vs 38.2 per 100 patient-years). The EAIR for invasive second primary malignancy was the same in patients with long-term benefit of therapy and other patients (1.7 per 100 patient-years). These findings indicate that patients with RRMM can experience long-term benefit with lenalidomide and dexamethasone treatment with manageable side effects.

TO THE EDITOR: Lenalidomide is a novel immune modulating drug (IMiD) that has demonstrated impressive antitumor activity in previously treated multiple myeloma and International Prognostic Scoring System low-risk and intermediate-1 risk deletion 5q myelodysplastic syndromes. The antileukemic effects of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) were recently reported in two ongoing phase II studies. 1,2 In the first study by Chanan-Khan et al, lenalidomide was given orally with a cyclic 25-mg regimen (day 1 to 21 of a 28-day cycle) in 45 patients with relapsed or refractory CLL; the overall response rate (ORR) was 47% with 9% of the patients attaining complete remission. In the other study by Ferrajoli et al, oral lenalidomide was administered at 10 mg daily for 28 days and dose escalated up to a maximum of 25 mg daily, in 45 patients with relapsed CLL who had received at least one purineanalog based regimen. The first 35 patients assessable for response had an ORR of 38% with 9% attaining complete remission. In both studies notable adverse reactions included tumor flare reaction (TFR) and tumor lysis syndrome (TLS). In the study by Chanan-Khan et al, TFR occurred in 58% (grade Յ 2, 50% and grade Ն 3, 8%) and TLS in 5% (all grade 3) of the patients. Ferrajoli et al reported 37% of TFR (grade Յ 2, 30% and grade Ն 3, 7%) and no TLS.We summarize here the development of TLS and TFR during lenalidomide therapy in CLL. TFR during lenalidomide therapy has been observed in CLL and small lymphocytic lymphoma (SLL). TFR occurs in the majority of lenalidomide-treated CLL patients, and is usually not severe and generally well managed with nonsteroidal antiinflammatory agents or steroids.Seven TLS episodes were observed among 260 CLL patients treated with lenalidomide to date. All seven patients had onset of TLS of varying severity during the first 15 days of treatment. Two patients also had concomitant TFR characterized by severe back and bone pain. TLS was complicated by acute renal failure and/or cardiac arrhythmia in three patients. Metabolic abnormalities and renal dysfunction resolved with supportive therapy in five patients; however, two patients died. Bulky disease, moderate renal insufficiency, and increased uric acid levels before therapy distinguished these seven patients from those who did not have TLS.Due to these findings, Celgene Corporation (Summit, NJ) temporarily suspended enrollment to its sponsored CLL trial (CC-5013-CLL-001) and an independent data monitoring committee (DMC) reviewed the data. The DMC recommended that, given the evidence of lenalidomide's significant activity in CLL in this and other trials, 1,2,5 the CLL-001 study should continue, but with modifications to define a better-tolerated lenalidomide dosing regimen. The DMC noted that similar reactions occurred with other immune modulating agents in CLL. 3,4 The use of low-dose-intensity regimens at the initiation of therapy and aggressive TLS prophylaxis and monitoring decreased the incidence of TL...

Lenalidomide is highly effective and generally well tolerated. Most adverse events occur early during the course of treatment and are manageable. Lenalidomide is not associated with peripheral neuropathy and has a lack of cumulative toxicity, making it an effective treatment option for long-term use in the management of MM and low/intermediate-1-risk MDS, specifically with chromosome 5q deletion with or without other cytogenetic abnormalities.

PurposeLenalidomide, a weak substrate of P-glycoprotein (P-gp) in vitro, is an oral anticancer drug eliminated predominantly via renal excretion as unchanged compound. The role of P-gp in lenalidomide disposition and the associated clinical relevance were evaluated.MethodsTwo phase I, crossover studies were conducted in healthy volunteers. In Study 1, subjects received lenalidomide (10 mg × 7 days) alone or with the P-gp substrate digoxin (0.5 mg on Day 5). In Study 2, subjects received lenalidomide (a single 25 mg dose) alone, the P-gp inhibitor quinidine (300–600 mg twice-daily × 5 days) plus lenalidomide (on Day 4), the P-gp inhibitor/substrate temsirolimus (a single 25 mg dose) alone, or lenalidomide plus temsirolimus. Pharmacokinetic and safety data were collected for lenalidomide and the co-administrated drugs.ResultsThere were no significant changes in the maximum concentration (Cmax) and area under the plasma concentration–time curve (AUC) of lenalidomide when co-administered with quinidine, digoxin, or temsirolimus. Neither the rate nor the capacity of lenalidomide renal excretion was affected by quinidine or temsirolimus, in addition lenalidomide absorption rate and bioavailability remained unchanged. Furthermore, lenalidomide had no significant effect on blood Cmax and AUC of temsirolimus and its active metabolite sirolimus (also a P-gp inhibitor/substrate). The Cmax of digoxin was slightly higher (+14 %) when administered with lenalidomide versus placebo. There were no other changes in digoxin pharmacokinetics upon co-administration with lenalidomide. No remarkable safety findings were observed.ConclusionsThere are no clinically significant pharmacokinetic interactions between lenalidomide and substrates or inhibitors of P-gp.

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