By William B. Ershler, MD
Synopsis: In a survey of consecutive myeloma patients from the Mayo Clinic on hypothetical constructs with varying expectations regarding overall survival benefit, toxicity, and financial burden, it was found that the majority of patients would not choose maintenance if toxicity was more than just mild and overall survival benefit was less than 1 year. Increasing financial burden (drug cost) also reduced the numbers that would choose maintenance therapy. Males were more likely than females to choose treatment in each of the scenarios presented.
Source: Burnette BL, et al. Treatment trade-offs in myeloma. A survey of consecutive patients about contemporary maintenance strategies. Cancer 2013;119:4308-4315.
Treatment recommendations for patients with multiple myeloma (MM) have evolved over the past 5 decades. Novel agents and combinations have led to patients living longer, and more effective initial therapy, including high-dose chemotherapy followed by autologous stem cell reconstitution, has more than doubled life expectancy for newly diagnosed patients compared to 2 decades ago. Despite this demonstrably greater success with initial therapy, the role of maintenance therapy has remained controversial. Early efforts using primarily a continuation of alkylating agent therapy showed little, if any, benefit.1,2 Subsequently, maintenance strategies incorporating interferon demonstrated prolongation in progression-free survival (PFS) by meta-analysis.3,4 The more recent use of novel agents such as thalidomide, lenalidomide, and bortezimib have proven effective and with less toxicity. Two randomized trials have demonstrated improved PFS with lenalidomide maintenance after autologous transplantation for MM.5,6 Yet, enhancement of overall survival (OS) remains to be conclusively demonstrated, and quality-of-life (QOL) data are lacking.
Although current myeloma maintenance strategies generally involve less toxic agents (lenalidomide, bortezimib) than their predecessors such as thalidomide and interferon, they are not without side effects and are very expensive. For example, a monthly supply of lenalidomide costs an estimated $10,000.
With the currently available information including effects on PFS, OS, and cost, investigators at Mayo Clinic conducted a systematic survey of MM patients regarding what constitutes a meaningful benefit that would make burdens of maintenance treatments (toxicity and cost) acceptable.
A self-administered survey was mailed to 1159 consecutive, living patients who had been evaluated at Mayo Clinic; 886 responded and 736 (66%) returned a completed questionnaire. The survey provided background information on the standard of care for MM and existing data on the effectiveness of maintenance.
Among responders, the most worrisome potential toxicity was identified as peripheral neuropathy by 27%, cytopenias by 24%, deep vein thrombosis by 20%, fatigue by 15%, nausea by 8%, and diarrhea/constipation by 7%. If treatment were to be provided free of cost, had no toxicity, and the OS benefit was ≤ 1 year, then 49% of patients indicated they would choose maintenance. In comparison, if treatment were associated with moderate toxicity, this proportion decreased to 42%. Adding a treatment cost of $25 per month decreased the proportion that would choose maintenance to 39% of patients. A moderate increase in cost to $250 per month did not affect the proportion choosing maintenance. However, with a marked increase in cost to $10,000 per month, the proportion who would choose maintenance with mild or moderate toxicity decreased to 32%. Across the different scenarios, male patients were more likely than female to choose maintenance therapy and older patients required a smaller increment in improved survival to opt for maintenance when compared to younger patients.
COMMENTARY
The current results indicated that willingness to receive maintenance treatment declined when actual benefits were provided in concrete numeric terms compared with a general statement of PFS benefit. The authors also observed that the magnitude of benefit required to consider maintenance was affected by cost and toxicity. The findings are sobering, but not all that surprising in light of the real but modest data on efficacy as honestly presented to study participants and the clear discussion of potential toxicity and costs. The findings should also be interpreted in the appropriate context. All of the patients had been evaluated at the Mayo Clinic, many of whom travelled great distances for consultation, if not treatment. Despite this common thread, responses came from patients at all stages, including those recently diagnosed and those who were in the terminal phase of illness. Nonetheless, it is important to recognize that patient choice is an essential element in the selection of treatment, and what might be considered standard therapy could be less desirable when quality of remaining life or financial considerations are factored in. This, of course, is relevant to all aspects of the physician/patient relationship. However, in the context of choosing maintenance therapy for patients with myeloma, this report provides current and relevant parameters. Although maintenance therapy is commonly selected, future research will hopefully define those who are most likely to benefit. For example, as suggested by the authors, those patients who had experienced an excellent response to initial intervention might be just the population for whom maintenance therapy is of limited benefit and should be withheld.7,8
References
- Treatment comparisons in the third MRC myelomatosis trial. Medical Research Council's Working Party on Leukaemia in Adults. Br J Cancer 1980;42:823-30.
- Cohen HJ, et al. Consolidation and maintenance therapy in multiple myeloma: Randomized comparison of a new approach to therapy after initial response to treatment. J Clin Oncol 1986;4:888-899.
- Myeloma Trialists' Collaborative Group. Interferon as therapy for multiple myeloma: An individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 2001;113:1020-1034.
- Fritz E, Ludwig H. Interferon-alpha treatment in multiple myeloma: Meta-analysis of 30 randomised trials among 3948 patients. Ann Oncol 2000;11:1427-1436.
- Attal M, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1782-1791.
- McCarthy PL, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1770-1781.
- Kyle RA. Role of maintenance therapy after autologous stem cell transplant for multiple myeloma: Lessons for cancer therapy. Mayo Clin Proc 2011;86:419-420.
- Rajkumar SV. Haematological cancer: Lenalidomide maintenance—perils of a premature denouement.Nat Rev Clin Oncol 2012;9:372-374.