An alternative dosing strategy of lenalidomide for patients with relapsed multiple myeloma

Field: Medicine (Health Sciences)

The treatment options for patients with multiple myeloma (MM) are rapidly evolving with thalidomide, lenalidomide and bortezomib used routinely in standard regimens. Such drugs have been credited with the improved survival of patients over the last 10 years (Kumar et al, 2008). In a pooled analysis of two large international randomized phase 3 clinical trials of 704 patients with relapsed MM (MM009/010), lenalidomide and dexamethasone demonstrated improvements in progression-free survival (PFS) (11·1 vs. 4·6 months), time to progression (TTP) (13·4 vs. 4·6 months) and overall survival (OS) (38·0 vs. 31·6 months) compared with high dose dexamethasone (Dimopoulos et al, 2009). As expected, this benefit was greater when used for patients at first relapse compared to those treated at later stages of their disease (Stadtmauer et al, 2009). Patients on trial protocol received lenalidomide 25 mg/d for 21 d of a 28-d cycle continuously until disease progression (median duration of response 10·1 months). Although lenalidomide was well tolerated, haematological toxicity was encountered and more frequent with multiple lines of prior therapy. The summary of product characteristics (SPC) recommends that lenalidomide dosing is interrupted in the event of grade 3 or 4 neutropenia or thrombocytopenia until recovery. At this point, the dose may be reduced to the next level (e.g. reducing from 25 to 15 mg/d). For isolated neutropenia, granulocyte-colony stimulating factor may be administered with no dose reduction. In the MM-009/010 studies, 33·1% of patients treated at first relapse and 38% treated at second or subsequent relapse required such reductions (Stadtmauer et al, 2009). It was recently discovered that lenalidomide exerts its anti-myeloma effect by altering the substrate specificity of cereblon, thus targeting new proteins for degradation, such as members of the Ikaros family of transcription factors (Lu et al, 2014). Key consequences are the loss of interferon regulatory factor-4, which plays a key role in MM growth and survival, and the up-regulation of interleukin-2 in T-cells (Lopez-Girona et al, 2011). Therefore, whilst the plasma half-life of lenalidomide is only 3–5 h (http://www.medicines.org.uk/emc/medicine/19841/SPC/Revlimid%C2%AE/), its efficacy on a daily dosing schedule may be explained by the kinetics of target binding and cereblon re-expression. Indeed, the cytotoxicity of lenalidomide is orchestrated by a multitude of effects, including its effects upon the bone marrow microenvironment, suggesting that alternative schedules of administration may be efficacious. As the cost of cancer drugs to the National Health Service is under constant scrutiny, we investigated an alternative dose modification schedule for lenalidomide whereby all patients commenced treatment at the recommended SPC dose but in the event of toxicity requiring dose modification, followed an alternate day schedule (Table 1). This was designed to maintain similar overall doses to the SPC recommendations but altered the schedule to offset the impact of non-linear pricing (British National Formulary cost of lenalidomide capsule + 20% Value Added Tax as of May 2011: 25 mg = £249·60; 15 mg = £226·80; 10 mg = £216·00; 5 mg = £204·00). Table 1 shows the total dose administered per cycle employing this alternative dose reduction schedule, compared to the SPC schedule. It can be seen that the alternative dosing schedule reduces the total dose per cycle by 13% and 21% at dose levels -1 and -2 respectively. All patients had measurable disease by International Myeloma Working Group (IMWG) criteria and response rates assessed by IMWG response criteria (Durie et al, 2006); TTP, PFS and OS were assessed according to IMWG consensus criteria (Rajkumar et al, 2011). Interphase fluorescence in situ hybridization was performed on CD138+ selected cells isolated by positive selection. Lenalidomide drug costs were calculated by the number of capsules prescribed over the treatment period. For clarity, the National Institute for Health and Care Excellence (NICE) pricing agreement, whereby costs after 26 cycles are reimbursed by the manufacturer (NICE, 2009) was not taken into consideration (for prices including this see Table S1). The equivalent cost if the SPC schedule (daily dosing) was followed was calculated for comparison. Dexamethasone or supportive care costs were not calculated, as this was not varied. Due to the retrospective nature of this study, quality of life data were not available. 39 sequential patients with a median age of 66 years (range 36–87) who had received a median of two prior lines of therapy (range 1–8) were treated using this approach. Baseline demographics are shown in Table 2. The majority of patients were treated at second or subsequent relapse in line with current NICE recommendations (NICE, 2009). Treatment was continued until clinical evidence of disease progression except for one patient who only received 2 cycles as induction prior to autologous stem cell transplant. 36 of the 39 patients fulfilled criteria of disease progression at time of analysis. A median of 12 (range 1–48) cycles were given prior to disease progression or data lock. The overall response rate (≥PR) was 85% with 3% achieving CR (Table 2). With a median follow up of 45 months, median PFS was 11·5 months and median OS was 36·5 months (Fig S1). The median duration of response was 11·4 months. 38 patients (97%) required a dose reduction, which was performed according to the alternative dosing strategy. The cost of lenalidomide for the whole cohort of 39 patients was £2,190,433·00, whereas the predicted cost if dose reductions had followed the SPC schedule would have been £2,947,361·80. This yielded a cost saving of £756,928·80, equating to £19,408·43 per patient treated. As the starting dose for both schedules were the same, cost-savings were only delivered in the event of dose modification for toxicity. In summary, we report the feasibility of an alternative dose reduction schedule of lenalidomide for myeloma patients who were treated at relapse. The recently published lenalidomide mechanism of action by cereblon inhibition supports re-examination of the clinical dosing schedule as the pharmacodynamics of multiple down-stream effects of cereblon binding remain to be elucidated. We conclude that, within the limits of this retrospective analysis, the efficacy of the alternative dosing schedule was in keeping with that reported for the standard schedule, but yielded significant cost savings. We recommend that this observation is confirmed prospectively. RP, JD, SC, DS, SDS, NR and KY were involved in treating patients and collecting data. KY, SDS and NR designed the treatment protocol; RP and IK analysed the data. All authors were involved with writing and approving the final manuscript. The authors declare no competing interests. Fig S1. Kaplan Meir analysis for patients treated by the alternate day dosing schedule. Table S1. Comparison of overall and mean per patient costs by schedule. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.