Geriatrics for the Oncologist is guest edited by Stuart Lichtman, MD, and developed in collaboration with the International Society of Geriatric Oncology (SIOG). Visit SIOG.org for more on geriatric oncology.
Myeloma is a disease of aging, with a median age at diagnosis in the United States of 69 years.1 As the population ages, forecasts estimate that, within 20 years, 3 of every 4 people diagnosed with multiple myeloma in the United States will be between the ages of 64 and 84 years.2 In anticipation of this major demographic shift, recent studies are exploring the utility of geriatric assessment to optimize therapy for older adults with multiple myeloma.
The advent of novel therapies has yielded significant improvements in overall survival in patients with multiple myeloma over the past 15 years,3 including among older adults.4 Yet challenges in treating transplant-ineligible older adults with multiple myeloma persist. Early mortality disproportionately affects older adults,4,5 and health-related quality of life in patients with myeloma is among the lowest reported in older adults diagnosed with cancer.6
Balancing Response and Toxicity
Geriatric assessment is showing promise as a tool to predict which individuals are at greater risk for toxicity of therapy and to guide dose modifications based on an individual’s vulnerability.— Tanya M. Wildes, MD, MSCI
Tweet this quote
Clinicians treating older adults with multiple myeloma must balance the goal of a deeper response to therapy with the greater risk of toxicity with more aggressive therapeutic combinations. In some studies of older adults treated with novel therapies, achieving a complete response is associated with longer survival.7,8 Yet in other studies, if the toxicity of therapy is high, the benefit of improved disease response on survival was negated.9,10
In a randomized trial of high- vs low-dose dexamethasone with lenalidomide (Revlimid), the overall response rate was higher with lenalidomide and high-dose dexamethasone, yet the 1-year survival was lower in this group, due to a substantially higher rate of toxicity.9 In a randomized trial of bortezomib (Velcade) and dexamethasone (Vd) vs bortezomib, thalidomide (Thalomid), and dexamethasone (VTD) vs bortezomib, melphalan, and prednisone (VMP), greater toxicity in the three-drug arms resulted in greater rates of drug discontinuation, with a similar overall response rate and overall survival among the three groups.10
Thus, the risk of toxicity of therapy is an important consideration in older adults with multiple myeloma. In a study of more than 1,400 older adults with newly diagnosed multiple myeloma, the occurrence of grade III/IV toxicity, particularly cardiac, infectious, and gastrointestinal toxicities, was associated with poorer survival.11 Toxicities are also associated with decrements in patient-reported quality of life.10,12 Conversely, with well-tolerated, effective therapy, health-related quality of life improvements are seen and sustained as long as the patient remains progression-free.13
Predicting Those at Risk
Geriatric assessment is showing promise as a tool to predict which individuals are at greater risk for toxicity of therapy and to guide dose modifications based on an individual’s vulnerability. In a pooled analysis of 869 patients enrolled in one of three clinical trials, Palumbo et al developed a tool to predict overall survival, incorporating the geriatric assessment domains of functional status and comorbidities.14 They examined the impact of age, dependence in activities of daily living, dependence in instrumental activities of daily living, and comorbidities measured with the Charlson Comorbidity Index.
Using the hazard ratios from the multivariable model, a scoring system was developed. Patients received 1 point for age between 76 and 80 years or 2 points for age 80. Dependence in two or more activities of daily living or three or more instrumental activities of daily living received 1 point each. A Charlson Comorbidity Index score of 2 or greater yielded 1 point. Older adults with 0 points were then categorized as fit; those with a score of 1 point were categorized as “intermediate fit”; those with a score of 2 or greater were categorized as “frail.”
This frailty score is both predictive and prognostic. Frail patients were more likely to experience grade 3 or greater nonhematologic toxicity of therapy (hazard ratio [HR] = 1.57, 95% confidence interval [CI]: 1.12–2.19) compared with fit patients and were more likely to discontinue therapy for causes other than disease progression or death (HR = 2.21, 95% CI: 1.57–3.09). Geriatric assessment was also prognostic, independent of International Staging System stage, adverse chromosomal abnormalities, and treatment; frail patients had a nearly threefold greater risk for death (HR = 2.88, 95% CI: 1.88–4.40, P < .001).
Interestingly, one of the studies was designed with a priori dose modifications based on age.15 The three arms were melphalan, prednisone, and lenalidomide (MPR); cyclophosphamide, prednisone, and lenalidomide (CPR); and lenalidomide and dexamethasone (Rd). Melphalan in the MPR arm, lenalidomide and cyclophosphamide in the CPR arm, and dexamethasone in the Rd arm had modifications based on age > 75 years. There were no significant differences in efficacy among the arms.
In exploratory analyses of toxicities, rates of hematologic toxicity were similar across the frailty categories. These findings support clinical trials designed to address the increasing risk of toxicity in more vulnerable subgroups. However, despite the empiric age-based dose modifications, the frail patients still had a greater risk of nonhematologic adverse events and drug discontinuation, suggesting further refinement of treatment stratification and dose modifications are needed.
Other studies have further supported the utility of assessment of geriatric parameters in predicting survival. In a study of 110 people older than age 65 with newly diagnosed multiple myeloma, comorbidities and dependence in instrumental activities of daily living were associated with an increased risk of death.16 Kleber et al developed and validated the Freiburg Comorbidity Index, which incorporates Karnofsky performance status, and pulmonary and renal disease; this index is prognostic, independent of the International Staging System.17,18
Closing Thoughts
Geriatric assessment is a promising tool to aid in tailoring treatment recommendations for older individuals with myeloma. Future research may demonstrate whether incorporating additional geriatric domains, including cognition, depression/anxiety, social support, falls, and polypharmacy, adds to predictive and prognostic tools and allows more precise, personalized therapy to maximize responses while minimizing the risk of toxicity. ■
Disclosure: Dr. Wildes reported no potential conflicts of interest.
References
1. National Cancer Institute: SEER Stat Fact Sheets: Myeloma. Available at http://seer.cancer.gov/statfacts/html.mulmy.html. Accessed March 2, 2016.
2. Rosenberg PS, Barker KA, Anderson WF: Future distribution of multiple myeloma in the United States by sex, age, and race/ethnicity. Blood 125:410-412, 2015.
3. Pulte D, Jansen L, Castro FA, et al: Trends in survival of multiple myeloma patients in Germany and the United States in the first decade of the 21st century. Br J Haematol 171:189-196, 2015.
4. Kumar SK, Dispenzieri A, Lacy MQ, et al: Continued improvement in survival in multiple myeloma: Changes in early mortality and outcomes in older patients. Leukemia 28:1122-1128, 2014.
5. Holmström MO, Gimsing P, Abildgaard N, et al: Causes of early death in multiple myeloma patients who are ineligible for high-dose therapy with hematopoietic stem cell support: A study based on the nationwide Danish Myeloma Database. Am J Hematol 90:E73-E74, 2015.
6. Kent EE, Ambs A, Mitchell SA, et al: Health-related quality of life in older adult survivors of selected cancers: Data from the SEER-MHOS linkage. Cancer 121:758-765, 2015.
7. Lopez A, Mateos MV, Oriol A, et al: Patterns of relapse and outcome of elderly multiple myeloma patients treated as front-line therapy with novel agents combinations. Leuk Res Rep 4:64-69, 2015.
8. Gay F, Larocca A, Wijermans P, et al: Complete response correlates with long-term progression-free and overall survival in elderly myeloma treated with novel agents: Analysis of 1175 patients. Blood 117:3025-3031, 2011.
9. Rajkumar SV, Jacobus S, Callander NS, et al: Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma. Lancet Oncol 11:29-37, 2010.
10. Niesvizky R, Flinn IW, Rifkin R, et al: Community-based phase IIIB trial of three upfront bortezomib-based myeloma regimens. J Clin Oncol 33:3921-3929, 2015.
11. Bringhen S, Mateos MV, Zweegman S, et al: Age and organ damage correlate with poor survival in myeloma patients: Meta-analysis of 1435 individual patient data from 4 randomized trials. Haematologica 98:980-987, 2013.
12. Delforge M, Dhawan R, Robinson D Jr, et al: Health-related quality of life in elderly, newly diagnosed multiple myeloma patients treated with VMP vs. MP: Results from the VISTA trial. Eur J Haematol 89:16-27, 2012.
13. Benboubker L, Dimopoulos MA, Dispenzieri A, et al: Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 371:906-917, 2014.
14. Palumbo A, Bringhen S, Mateos MV, et al: Geriatric assessment predicts survival and toxicities in elderly myeloma patients: An International Myeloma Working Group report. Blood 125:2068-2074, 2015.
15. Magarotto V, Bringhen S, Offidani M, et al: Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood 127:1102-1108, 2016.
16. Bila J, Jelicic J, Djurasinovic V, et al: Prognostic effect of comorbidity indices in elderly patients with multiple myeloma. Clin Lymphoma Myeloma Leuk 15:416-419, 2015.
17. Kleber M, Ihorst G, Terhorst M, et al: Comorbidity as a prognostic variable in multiple myeloma: Comparative evaluation of common comorbidity scores and use of a novel MM-comorbidity score. Blood Cancer J 1:e35, 2011.
18. Kleber M, Ihorst G, Gross B, et al: Validation of the Freiburg Comorbidity Index in 466 multiple myeloma patients and combination with the international staging system are highly predictive for outcome. Clin Lymphoma Myeloma Leuk 13:541-551, 2013.
