TO THE EDITOR: The study by Roy and colleagues (June 2015) presented a model framework to estimate the costs of treatment for relapsed and/or refractory multiple myeloma.1 We believe the assumptions applied in the study, particularly those regarding duration of therapy, lead to erroneous conclusions.
In our view, the major methodological flaw is in the attempt to standardize median progression-free survival (PFS) from different trials into a single measure of “efficacy.” To do this, the authors attempted to calculate the duration of therapy theoretically needed to achieve 12 months of PFS. This was done using the reported PFS in each trial, which ranged from 3.7 months to 26.3 months.
First, the assumptions used to calculate the theoretical duration of therapy are not consistent with current clinical practice in relapsed and/or refractory multiple myeloma. As such, this leads to a misrepresentation of the costs associated with each treatment regimen. For example, for regimens with PFS <12 months, the authors assumed that patients would be retreated with the same regimen repeatedly, and with the same PFS benefit each time, until 12 months of PFS are reached. In clinical practice, and consistent with the National Comprehensive Cancer Network guidelines in multiple myeloma, patients whose disease progresses with a given regimen are switched to a different therapy.2 For regimens with PFS >12 months and duration of therapy of less than the PFS period, the authors assumed that patients would only be treated with the medication for a fraction of the 12-month period (equivalent to [median duration of therapy/median PFS] × 12 months), even if the duration of therapy was >12 months in the trial. In practice, if the duration of therapy is >12 months, we would expect a patient to receive treatment for the full first year, not only for a fraction of that time.
Second, the analysis is based on comparisons across studies with different populations and inclusion/exclusion criteria. Although the authors acknowledge this fact, no attempt is made to correct for these differences. For example, the median number of previous therapies ranged from 1.7 to 5 across the included trials.3-5 However, even though it has been shown that a greater number of previous therapies are associated with worse outcomes,6 no statistical adjustment was done before comparing the efficacy results.
Finally, the authors assume that the rate of adverse events remains constant over time. No evidence is shown to support this assumption. In practice, it is often the case that the majority of adverse events are experienced within the first few cycles of therapy.7,8 In addition, there is no mention in the article of the economic benefit of treatments that prolong PFS and delay disease progression.9 Finally, no uncertainty or scenario analyses are offered around the base-case assumptions.
In summary, this analysis uses multiple assumptions inconsistent with current practice and experience with studied regimens, and makes a comparison of data across studies with different patient populations. This raises questions as to the validity of the conclusions.
Safiya Abouzaid, PharmD, MPH
Craig Gibson, PhD
Yasir Nagarwala, MD
Celgene Corporation, Summit, NJ
Disclosure: The authors are employees of and own stock of Celgene Corporation, the manufacturer of lenalidomide.
1. Roy A, Kish JK, Bloudek L, et al. Estimating the costs of therapy in patients with relapsed and/or refractory multiple myeloma: a model framework. Am Health Drug Benefits. 2015;8(4):204-215.
2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): multiple myeloma. Version 2.2016. September 22, 2015. www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed July 20, 2015.
3. Pomalyst (pomalidomide) capsules [prescribing information]. Summit, NJ: Celgene Corporation; April 2015.
4. San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:1055-1066.
5. San-Miguel JF, Hungria VTM, Yoon S-S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15:1195-1206. Erratum in: Lancet Oncol. 2015;16:e6.
6. Kumar SK, Lee JH, Lahuerta JJ, et al; for the International Myeloma Working Group. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter International Myeloma Working Group study. Leukemia. 2012;26:149-157. Erratum in: Leukemia. 2012;26:1153.
7. San-Miguel JF, Dimopoulos MA, Stadtmauer EA, et al. Effects of lenalidomide and dexamethasone treatment duration on survival in patients with relapsed or refractory multiple myeloma treated with lenalidomide and dexamethasone. Clin Lymphoma Myeloma Leuk. 2011;11:38-43.
8. Ishak J, Dimopoulos MA, Weber D, et al. Declining rates of adverse events and dose modifications with lenalidomide in combination with dexamethasone. Blood. 2008;112. Abstract 3708.
9. Arikian SR, Milentijevic D, Binder G, et al. Patterns of total cost and economic consequences of progression for patients with newly diagnosed multiple myeloma. Curr Med Res Opin. 2015;31:1105-1115.
THE AUTHORS RESPOND: A response from the authors can be found here.