which to base economic assessment of the products available to treat this hematologic

Size: px

Start display at page:

Download "which to base economic assessment of the products available to treat this hematologic"

Brice Tyler
6 years ago
Views:

1 special feature Measuring Value of Multiple Myeloma Therapies by Gary M. Owens, MD, Gary Owens Associates As recent therapies for multiple myeloma (MM) have provided significant improvements in the prognosis for patients who previously faced a very short life expectancy, so too have they raised payor awareness of the product category. While the advances in five-year survival rates wrought by the newer MM therapies compare favorably with many other conditions, payors nevertheless need to gain a sense of comfort regarding the value generated by these treatments. Furthermore, in order to make reimbursement and coverage decisions, payors need accurate information upon which to base economic and clinical assessment of the products available to treat this hematologic condition. Sound decision making mandates knowledge of the pitfalls associated with some early attempts at measuring this value and some of the important practices to follow in assessing value. Due to the clinical complexity of MM, the need for individualization of therapy based on patient comorbidities, and the lack of head-to-head randomized clinical trials, comparisons of treatments are difficult. Adding to the challenge is the number of different endpoints, trial designs, and patient populations used in clinical studies. Finally, the number of therapeutic choices showing efficacy after previous therapies have become ineffective is significant, and their impact on outcomes can confound the survival metrics. Reviews of the economic literature assessing MM treatments suggest that more high-quality economic assessments, particularly of the more recently approved MM treatments, are needed. Background: What Is Multiple Myeloma? Multiple myeloma is a malignancy of plasma cells characterized by the production of abnormal immunoglobulins. Due to the proliferation of myeloma cells, the malignant plasma 10

2 cells crowd out healthy blood cells, which may lead to anemia, leukopenia, and bone loss. The goal of treatment for MM patients is to relieve disease symptoms and complications such as renal impairment, avoid complications arising from therapy (including disease relapse or progression), and extend patient survival. 1 Of the three major types of hematologic cancers (i.e., leukemia, lymphoma, and MM), MM is the least common; however, the frequency of the disease is increasing. 2 The five-year survival rate for patients diagnosed with MM is approximately 35%, with significant improvements being achieved over the past decade, though this varies by stage at diagnosis (Figure 1). 3 Improvements in prognosis have occurred because of the introduction of newer therapies such as pulse corticosteroids, immunomodulators (thalidomide, lenalidomide), and a proteasome inhibitor (bortezomib). Brenner and colleagues attempted to project changes in survival rates as a result of the introduction of these newer therapies in patients with MM who were diagnosed between 2006 and Using data from the Surveillance, Epidemiology, and End Results (SEER) database and a modelbased projection method, they projected five- and 10-year relative survival expectations of patients with MM in the U.S. The results of their prediction model indicate that patients with MM, particularly those diagnosed at age 45 or younger, have five- and 10-year survival rates that are much higher than previously expected. 4 Treatment Overview According to guidelines published by the National Comprehensive Network (NCCN), MM patients with newly diagnosed, active disease are recommended to receive induction therapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) in select patients. In patients eligible for ASCT, NCCN guidelines indicate that there are three evidence-based recommendations for induction therapy prior to ASCT: bortezomib-, lenalidomide-, and thalidomide-containing induction regimens. 5 Lenalidomide +, as well as bortezomib +, carry category 1 recommendations for induction therapy in transplant candidates, while the thalidomide + regimen carries a category 2B recommendation. 5 In patients who are not candidates for ASCT frequently those who are older than age 65 or who have significant comorbidities bortezomib or lenalidomide, in combination with melphalan and prednisone, are recommended as treatment options by NCCN. 5 Increasingly, evidence has shown that patients receiving these novel therapies earlier in their treatment, as well as those who are able to remain on therapy longer, are able to achieve better outcomes. To that end, a variety of studies have been undertaken to devise new regimens to avoid treatment discontinuation due to side effects such as peripheral neuropathy, which was commonly seen in the thalidomide and bortezomib trials. Despite the progress associated with the novel therapies, virtually every patient will ultimately experience relapse or disease progression. Fortunately, these patients (and in many cases, even patients refractory to their previous therapy) often can regain control over the disease by undergoing a new course of therapy. However, each relapse does leave the patient with Figure 1. Incidence and Five-Year Survival Rates for Five Types INCIDENCE RATE (per 100,000) Incidence (per 100,000) Multiple Myeloma Metastatic Breast 59% Colorectal Five-Year Overall Survival Rate Lung Female Breast 100% Sources: SEER Statistics Review, 2010; American Society, 2010; Centers for Disease Control and Prevention, % 80% 70% 60% 50% 40% 30% 20% 10% 0% managedcareoncology.com 11

3 a shorter likely interval until the next relapse, essentially moving myeloma toward a chronic treatment model. Clinical Endpoints: Response, Progression, and Survival In 2008, the American Society of Hematology and the U.S. Food and Drug Administration (FDA) made joint recommendations regarding preferred endpoints in clinical trials investigating new therapies for the treatment of MM, with the goal of providing guidance on which endpoints may be used for claims of efficacy. 6 While complete response (CR) was a traditional clinical trial endpoint, it was not among the primary endpoints endorsed by the working group due to concerns with biomarker test reliability and ambiguous relationship with survival. 6-8 Instead, the working group recommended several possible endpoints as appropriate, including time to progression (TTP), progression-free survival, and overall survival (OS), albeit acknowledging the challenges surrounding use of OS. Primarily, these challenges are the long follow-up necessary to achieve median OS, and the impact of subsequent therapies that complicate the ability to cleanly interpret trial findings. 6 Consequently, these barriers with OS limit its potential for use in clinical trials and require consideration of more practical endpoints. Duration of therapy was not selected as a valid endpoint. TTP is a practical endpoint to define clinical benefit, and research indicates TTP may be a good predictor of longer-term survival in well-designed clinical trials. 8 Compared with the biomarker-based endpoint CR, TTP provides a more relevant assessment of treatment outcomes by providing a gauge of clinically meaningful progression in patients without the impractical confines presented by measuring OS. 6 Based on these considerations, the FDA has approved both lenalidomide and bortezomib in MM with TTP as the primary endpoint. Challenges in Determining Costs and Cost-Effectiveness of MM Treatment Though MM remains incurable, recent advances in MM treatment improved survival benefits to such a degree that MM is now viewed as a chronic illness, particularly in younger individuals. 9 These survival benefits mean patients who used to remain on therapy and live for months now survive, and receive therapy, for years. In tandem with this rise in survival benefit is the diligent appraisal by payors of MM and associated therapies in terms of maximizing value for all stakeholders. The two major components of this diligent appraisal of value are costs and outcomes. Payors require timely and accurate information on costs and outcomes in order to make well-informed decisions. This has proven difficult in MM, as evidenced by a critique of the available economic literature in MM finding that high-quality economic evaluations particularly those related to the recently approved novel therapies are lacking. 10,11 To elaborate further on this challenge, recent economic literature on MM is presented and opportunities for enhancement are described in the following paragraphs. To assess the budget impact of the direct costs of lenalidomide compared with bortezomib in the relapsed/refractory setting, Fullerton and colleagues undertook two budget impact analyses. The first compared bortezomib with lenalidomide The second evaluated the direct cost of bortezomib (VEL), bortezomib + pegylated liposomal doxorubicin (VEL + DOX), lenalidomide + (REV + DEX), and thalidomide + (THAL + DEX) for the treatment of MM. Results of both budget impact analyses suggested that, of the treatments compared, VEL was the least expensive treatment because it was used for the fewest number of cycles. 13 Both analyses involve methodological choices that merit consideration. Comparing two treatment regimens given to patients over two time periods of varying length (in this instance, 18 weeks for bortezomib vs. 44 weeks for lenalidomide + ), does not address costs between 18 to 44 weeks for surviving patients and Table 1. Results from Clinical Studies Used in Wang et al. 15 Treatment bortezomib + melphalan + prednisone San Miguel, 2008 (VISTA) 17 Palumbo, 2009 (MM-015) 16 Median follow-up 16.3 months 9.4 months TTP HR* (p value) 0.48 NR lenalidomide + melphalan + prednisone followed by lenalidomide maintenance PFS HR* NR % of patients with CR in treatment group (p value) 30% 18% Median OS not reached not reached CR: complete response; HR: hazard ratio; NR: not reported; OS: overall survival; PFS: progression-free survival; TTP: time to progression; VISTA: Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone *primary endpoint 12

4 Table 2. Comparison of Short-Term Follow-Up Studies the costs of therapy discontinuation, especially since patients often switch therapies when they are no longer effective or adverse events occur.* Providing cost estimates for utilization occurring from week 18 to week 44 for the patients treated with bortezomib would make comparisons more meaningful. In addition, the selection of duration of therapy as an endpoint for product comparison raises questions since, among other concerns, it introduces a bias in favor of the less tolerable therapy a particularly concerning method when studies show the benefits from continuing therapy. Another example of analytical assessment in MM was a recent cost-effectiveness analysis by Wang and colleagues (Table 1). Wang and colleagues used an indirect treatment comparison to determine the costeffectiveness of a bortezomib + melphalan + prednisone (VMP) regimen compared with a lenalidomide + melphalan + prednisone regimen followed by maintenance therapy with lenalidomide (MPR-R) in newly Richardson, 2005 Dimopolous, 2007 Weber, 2007 (APEX) 18 (MM-010) 19 (MM-009) 20 Treatment bortezomib lenalidomide + lenalidomide + Median follow-up 9 months^ 16.4 months 17.6 months TTP* (p value) % of patients with CR in treatment group (p value) 6.22 months 11.3 months 11.1 months 6% 15.9% 14.1% Median OS (p value) not reached not reached 29.6 months OS HR 0.57 (p = 0.001) 0.66 (p = 0.03) 0.44 (p = 0.03) APEX: Assessment of Proteasome Inhibition for Extending Remissions; CR: complete response; HR: hazard ratio; OS: overall survival; TTP: time to progression *TTP was the primary endpoint; ^median follow-up was not provided in the Richardson (2005) study but was calculated based on the total treatment time of 273 days for patients in the bortezomib treatment group. diagnosed MM patients not eligible for ASCT. 15 The analysis does not reflect that the studies involved two different treatment populations with varying lengths of follow-up: (1) VMP patients who were followed for a median of 16.3 months (VISTA study) and (2) MPR-R patients who were followed for a median of 9.4 months (MM-015 trial). A further challenge is that the studies used markedly different regimens and dosing for the melphalan arm, which appears to have played an important role in the metrics, Table 3. Comparison of Long-Term Follow-Up Studies Richardson, and particularly the timing, of the outcomes, thus complicating the comparison. Because median OS was not yet reached in the MM-015 trial 16 the OS hazard ratio (HR) for the MPR-R treatment group was set to 1.0, indicating no survival benefit in Wang s model. This decision to set the HR to 1.0 is not consistent with available evidence, and this choice of methodology predetermines the outcome, producing a calculation based on these assumptions that VMP was nearly half the cost of MPR-R ($119,102 vs. $241,247), while being nearly 25% more effective (the number of life years saved on VMP was set to 4.2, as compared with 3.4 on MPR-R). 15 A more appropriate approach could involve comparing the same endpoints and/or using a similar follow-up period, which would yield vastly different costeffectiveness ratios. For example, an indirect comparison of trials in which TTP was the primary endpoint indicates that patients who received lenalidomide + had a longer TTP than patients who received bortezomib (Table 2). Similarly, results from a long-term analysis indicate that TTP was more than twice as long in patients in the lenalidomide + group compared with the bortezomib group (Table 3). Dimopolous, 2009^22 Treatment bortezomib lenalidomide + Median follow-up 36 months 48 months TTP* (p value) 6.2 months (NR) 13.4 months % of patients with CR in treatment group (p value) 9% (NR) 15% Median OS (p value) 29.8 months (p = 0.27) 38.0 months (p = 0.045) CR: complete response; NR: not reported; OS: overall survival; TTP: time to progression ^Pooled, long-term results from patients in both MM-009 and MM-010 *TTP was the primary endpoint. *In a follow-up article quoting the results from the Fullerton et al. (2007) research, the bortezomib combination regimen was mistakenly referred to as bortezomib + when, in fact, the original study assessed the costs of bortezomib + doxorubicin. 13,14 managedcareoncology.com 13

5 Similarly, a subgroup analysis in relapsed/refractory myeloma by Stadtmauer showed that lenalidomide +, when used for patients with only one previous relapse, achieved a TTP of 17.1 months, while Richardson found that bortezomib achieved seven months for similar patients. 23 A third, more recent example of efforts to assess value in MM was described by Durie et al., where treatment costs of bortezomib and lenalidomide + were compared over a 12-month period in relapsed/ refractory patients. 24 In this analysis, which did use common time periods and validated endpoints for comparison purposes, drug costs were found to be comparable for the two regimens throughout the period, while medical costs (treatment costs as well as adverse event management) were more than $20,000 higher for bortezomib. Implications for Payors In order to determine the best valuebased strategies for the treatment of MM patients, payors must continue to assess the evolving landscape of treatment options and consider both clinical benefits and treatment costs in their analyses. Unfortunately, the amount of evidence currently available for payors to make informed valued determinations for MM therapies is sparse, and the quality of much of the evidence to date is suboptimal. Comparisons of available treatments using budget impact and costeffectiveness analyses are most useful if the comparisons are transparent, accurate, and credible. Analyses would be more impactful if they compared common time periods, particularly since myeloma patients typically continue onto another therapy when they experience relapse. Analyses also would be more impactful if they evaluated common, valid endpoints for the therapies. This would allow for a more appropriate total cost-of-care analysis from the payor perspective. Further research is needed to provide useful comparisons that can aid payor decision making in assessing the value of these effective agents, and other new agents that are transforming these cancers into more readily treatable conditions. References 1. Multiple myeloma. National Center for Biotechnology Information website. Accessed May 5, Plasma cell neoplasms (including multiple myeloma) treatment. National Institute website. Accessed February 26, Multiple myeloma. American Society website. Accessed May 2, Brenner H, Gondos A, and Pulte D. Expected long-term survival of patients diagnosed with multiple myeloma in Haematologica. 2009;94: NCCN guidelines version : multiple myeloma. National Comprehensive Network website. Accessed May 2, Anderson KC, Kyle RA, Rajkumar SV, et al. Clinically relevant end points and new drug approvals for myeloma. Leukemia. 2008;22: Barlogie B, Tricot G. Complete response in myeloma: a Trojan horse? Blood. 2006;108(7): Kane RC, Bross PF, Farrell AT, Pazdur R. Velcade : U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist. 2003;8(6): Kenney JT. Advances in the management of multiple myeloma: implications for payors. Am Health Drug Benefit. 2011;4(2)(suppl 4):S59-S Galutney JG, Redekop WK, Sonneveld P, Uyl-de Groot CA. Critical review of economic evaluations in multiple myeloma: an overview of the economic evidence and quality of the methodology. Eur J. 2011; doi: /j.ejca Messori A, Maratea D, Nozzoli C, Bosi A. The role of bortezomib, thalidomide, and lenalidomide in the management of multiple myeloma. Pharmacoeconomics. 2011;29(4): Fullerton DSP, Trautman H, Huang H, et al. A budget impact model comparing resource utilization of four approved therapies for multiple myeloma (MM) in the U.S. Blood. 2007;110(11): abstr Fullerton DS, Huleatt H, Marantz JL, et al. Treatment of relapsed myeloma: a budget impact model comparing single agent bortezomib with combination lenalidomide and high-dose. J Manag Care Pharm. 2007;13(8): Cook R. Economic and clinical impact of multiple myeloma to managed care. J Manag Care Pharm Sep;14(7)(suppl): Wang ST, Huang H, Ba-Mancini A, et al. The cost-effectiveness of bortezomib plus melphalan and prednisone versus lenalidomide plus melphalan and prednisone with continuous lenalidomide maintenance treatment for the initial treatment of multiple myeloma in the United States. Presented at American Society of Hematology; December 10-13, 2010; San Diego, California. 16. Palumbo A, Dimopoulos M, Delforge M, et al. A phase 3 study to determine the efficacy and safety of lenalidomide in combination with melphalan and prednisone followed by lenalidomide (MPR-R) in patients 65 years with newly diagnosed multiple myeloma (NDMM). Presented at American Society of Hematology; December 5-8, 2009; New Orleans, Louisiana. 17. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359: Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose for relapsed multiple myeloma. N Engl J Med. 2005;352(24): Dimopolous M, Spencer A, Attal M, et al. Lenalidomide plus for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357: Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus for relapsed multiple myeloma in North America. N Engl J Med. 2007;357: Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110: Dimopolous MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase 3 trials of lenalidomide plus in patients with relapsed or refractory multiple myeloma. Leukemia. 2009;23: Stadtmauer E, Weber DM, Niesvizky R, et al. Comparison of lenalidomide plus therapy used at first relapse versus later salvage therapy in relapsed or refractory multiple myeloma patients. ASCO J Clin Oncol. 2009;27:15s,(suppl) abstr Durie BGM, Borrello I, Binder G, Khan ZM. Treatment cost comparison in relapsed multiple myeloma. Presented at International Myeloma Working Group; May 3-6, 2011; Paris, France. 14

Treatment of elderly multiple myeloma patients

SAMO Interdisciplinary Workshop on Myeloma March 30 th -31 st 2012, Seehotel Hermitage, Lucerne Treatment of elderly multiple myeloma patients Federica Cavallo, MD, PhD Federica Cavallo, MD, PhD Division