An Alternate Day Dosing Strategy for Lenalidomide in Multiple Myeloma Improves Cost-Effectiveness Whilst Maintaining Efficacy,
Authors: Popat Rakesh , Dickson Jenny , Khan Iftekhar , Cheesman Simon , Percy Laura , Moore Sally , D'Sa Shirley , Rabin Neil , Yong Kwee 
Published: October 2019

Abstract
Abstract 4201

Introduction
Lenalidomide and dexamethasone is an established treatment for multiple myeloma (MM). We investigated whether changing the dosing schedule reduced treatment costs whilst maintaining efficacy. According to the summary of product characteristics (SPC), the recommended starting dose of lenalidomide is 25mg/day for 21 days every 4 weeks. For grade 3/4 adverse events (AEs), lenalidomide is interrupted until recovery to grade 1 and then dose reduced to 15mg/day. For each subsequent grade 3/4 AE, a further 5mg/day reduction is advised. GCSF is permitted for isolated neutropenia. Within its licensed indication, patients remain on treatment until disease progression (median 10.1 months); however 38% require at least 1 lenalidomide dose reduction due to AEs (Dimopoulos et al. Leukemia 2009). In the UK, the National Institute for Clinical Excellence recommends lenalidomide and dexamethasone at second and subsequent relapse only, with the manufacturer bearing costs after 26 cycles. The incremental cost-effectiveness ratio (ICER) is £43,800 per QALY gained, but at first relapse was deemed too high (more than £69,000 per QALY gained) when compared to bortezomib. The UK price per capsule of lenalidomide (including 20% tax) and the USD equivalent (exchange rate August 2011) is: 25mg £249.60 ($407.56); 15mg £226.80 ($370.25). We therefore investigated the efficacy and costs of alternate day dosing in patients requiring modifications due to grade 3/4 AEs.

Methods
This was a retrospective review of patients treated with lenalidomide and dexamethasone for relapsed MM in a single UK centre. Treatment commenced with lenalidomide 25mg daily for 21 days per cycle and dexamethasone as per SPC. Upon grade 3/4 AE, lenalidomide was interrupted until recovery to grade 1 toxicity. Dosing was then recommenced at 25mg alternate days instead of 15mg daily. Subsequent dose reductions of 5 mg were made on the alternate day schedule (i.e. down to 15mg, then 10mg, then 5mg on alternate days). The efficacy of this regimen was assessed by IMW response criteria, time to progression (TTP), progression free survival (PFS) and overall survival (OS) according to IMW consensus criteria.

Results
A total of 42 patients received lenalidomide and dexamethasone of which 39 were evaluable for assessment (2 non-secretory MM, 1 Waldenstroms Macroglobulinaemia). The median age was 68 years (range 37–85) and the median number of prior lines of therapy were 2 (range 1–8). The overall response rate was 85% (PR 59%; VGPR 23%; CR 3%). After a median follow-up of 9.1 months, the median OS was 26.3 months (lower 95% CI of 24.4 months); PFS was 7.7 months (95% CI 4.9–11.6); and TTP was 11.8 months (lower 95% CI of 7.9). The upper 95% values for OS and TTP were not estimated due to few events. The 2 year OS rate was 82.7%. Patients received a median of 6 cycles over 11.7 months with a median duration of response of 7.1 months. These results are comparable to the MM-009/010 phase 3 trials (median TTP 13.4 months; PFS 11.1 months), bearing in mind that our patients were more heavily pre-treated (7% of our patients had 1 prior line compared to 18% in the MM-009/010 trials). 62% of patients required lenalidomide dose modification for AEs (approx. 1.5 times more than MM-009/010). The actual total cost of lenalidomide was £1,450,665.60 ($2,368,901.32) whereas if dose modification according to the SPC was followed, the predicted cost would be £1,914,987.60 ($3,128,254.42). This gives a cost saving of £464,322.00 ($758,615.19) equating to £11,905.69 ($19,455.51) per patient treated. Full cost-effective analysis will be presented at the meeting.

Conclusions
Whilst lenalidomide and dexamethasone is an effective treatment, dose modifications are required for AEs. Modifying the dosing schedule to alternate days rather than daily dosing at a lower dose resulted in a significant cost saving of £11,905.69 ($19,455.51) per patient treated. Such modifications were more frequent in our dataset due to the heterogeneous characteristics of non-trial patients. Hence this cost-benefit becomes more relevant in those with impaired bone marrow/ renal function and performance status. By making this treatment more affordable this dosing strategy may allow access at an earlier stage in treatment by reducing the ICER per QALY gained. Given the similar efficacy to the conventional dosing scheme, this may represent an alternative and more cost effective way of prescribing.

Disclosures:
Off Label Use: An alternative method of dosing revlimid.