Multiple myeloma is more prevalent in the older population; the median age of diagnosis is 69 years, and 35% of patients are age 75 or older at diagnosis.¹  Older individuals may have unique needs that should be considered in developing a treatment plan. But what is meant by “older?” There is great variation in fitness and overall health status among older adults of the same age, pointing to the need to examine factors other than age to identify those for whom risk-adapted therapies are appropriate.

One of these factors is frailty. Dr. Tanya Wildes (Washington School of Medicine, St. Louis) addressed issues related to frailty in a presentation titled “Unique Considerations for Management of Multiple Myeloma in Older Adults” at ASCO 2021. These issues include identifying frail and at-risk patients, improving frailty measures, and developing therapies that neither overtreat nor undertreat.

In 2015, the International Myeloma Working Group developed the IMWG Frailty Score Calculator. This assessment includes age, comorbidities, and the ability to carry out activities of daily living, such as bathing, food preparation, and managing medications. Based on their score, patients are categorized as fit, intermediate-fit, or frail.^1,2  While the IMWG assessment has been helpful for clinicians, Dr. Wildes recommends assessing additional factors to further identify those at greater risk while optimally treating those who can tolerate more intensive therapy. These factors include polypharmacy, cognitive impairment, falls, psychological health, and social frailty.

Polypharmacy, the presence of four or more medications, is an independent risk factor for adverse outcomes. The median number of medications taken by older myeloma patients is ten.³ Polypharmacy is associated with an increased risk of drug reactions, drug-drug interactions, falls, and poorer adherence to other medications, including lenalidomide.

Cognitive impairment can affect patients’ abilities to care for themselves, including the capability to adhere to medication schedules.⁴ Although there is little data on cognitive impairment in older adults with myeloma, Dr. Wildes pointed out that, in blood cancers overall, cognitive impairment is associated with poorer survival. For many patients, cognitive impairment worsens during induction. A decrease in cognitive functioning was self-reported by 49% to 57% of patients in the MAIA study.⁵

Fall risk is an important consideration. Dr. Wildes shared the results of a Medicare Health Outcomes Survey that showed that older myeloma patients are more likely than matched controls to suffer falls. Bortezomib, which increases the risk of peripheral neuropathy, was associated with a 30% increased risk of falls, but patients who reported fatigue, depression, and poor general health were also more likely to experience falls.

Psychological distress and its association with survival in myeloma patients was the subject of a recently published paper in Clinical Lymphoma, Myeloma & Leukemia.⁶ The researchers found that a higher level of distress was associated with a decreased survival rate. In discussing the needs of older adults, Dr. Wildes spoke of the prevalence of depression, which occurs in approximately 30% of older newly diagnosed myeloma patients. The impact goes beyond a poorer quality of life; depression is also associated with an increased risk of falls and poorer adherence to lenalidomide.

Social frailty refers to the loss of resources that fulfill social needs, such as friendships, family relationships, and feeling helpful to others. As with psychological distress, older adults who are vulnerable to social frailty are more likely to have poorer overall survival.

Interventions to address polypharmacy, cognitive impairment, falls, psychological health, and social frailty could result in an improved quality of life for older patients and reduce the risk of adverse outcomes. For example, the risks associated with cognitive impairment can be minimized by the use of written instructions, repetition, and routine and by actively involving family members and case managers in a patient’s care.⁴  Dr. Wildes discussed how collaboration with a pharmacist can reduce the impact of polypharmacy.

There are many treatment options for older adults with myeloma. Selecting the best therapy means balancing efficacy and toxicity against the background of a patient’s level of fitness or frailty. Fit patients can be treated with aggressive therapies, including autologous stem cell transplant, but less toxic therapies should be considered for frail patients. A review of the literature by Dr. Smith Giri and colleagues analyzed the efficacy and toxicity of nearly 30 randomized trials. The combination of daratumumab, lenalidomide, and dexamethasone was found to be optimal for frail patients.⁷

A recent study reported in Blood showed that an adjusted dose schedule of lenalidomide and dexamethasone in older myeloma patients can be considered for intermediate-fit patients. Induction followed by maintenance therapy of reduced-dose lenalidomide without dexamethasone was associated with similar responses and a longer event-free survival compared to continuous lenalidomide with dexamethasone.⁸

Researchers continue to explore other methods of assessing frailty. Bonello and colleagues have reported on objective methods, including a measure of sarcopenia, a condition marked by a decline of muscle mass and function. Although they are still at an experimental stage, laboratory-based biomarkers, such as telomere length, cell cycle arrest, and inflammation associated with aging, are also being investigated.⁹

In summary, age is not synonymous with frailty. Frailty is an important consideration in choosing a myeloma therapy that balances efficacy with toxicity. Frailty can be evaluated in a variety of ways, and new assessment methods are being researched. Perhaps most importantly, an awareness of factors that contribute to frailty will empower myeloma patients and their care partners to seek interventions that improve quality of life and enable them to benefit from the most effective therapies.

REFERENCES

1. Rosko A, Giralt S, Mateos MV, Dispenzieri A. Myeloma in Elderly Patients: When Less Is More and More Is More. Am Soc Clin Oncol Educ Book. 2017;37:575-585. doi:10.1200/EDBK_175171

2. Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report [published correction appears in Blood. 2016 Mar 3;127(9):1213] [published correction appears in Blood. 2016 Mar 3;127(9):1213] [published correction appears in Blood. 2016 Aug 18;128(7):1020]. Blood. 2015;125(13):2068-2074. doi:10.1182/blood-2014-12-615187

3. Wildes TM, Artz AS. Characterize, Optimize, and Harmonize: Caring for Older Adults With Hematologic Malignancies. Am Soc Clin Oncol Educ Book. 2021;41:1-9. doi:10.1200/EDBK_320141

4. Hshieh TT, Jung WF, Grande LJ, et al. Prevalence of Cognitive Impairment and Association With Survival Among Older Patients With Hematologic Cancers. JAMA Oncol. 2018;4(5):686-693. doi:10.1001/jamaoncol.2017.5674

5. Perrot A, Facon T, Plesner T, et al. Health-Related Quality of Life in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma: Findings From the Phase III MAIA Trial. J Clin Oncol. 2021;39(3):227-237. doi:10.1200/JCO.20.01370

6. Richter J, Sanchez L, Biran N, et al. Prevalence and Survival Impact of Self-Reported Symptom and Psychological Distress Among Patients With Multiple Myeloma. Clin Lymphoma Myeloma Leuk. 2021;21(3):e284-e289. doi:10.1016/j.clml.2020.11.021

7. Giri S, Aryal MR, Yu H, et al. Efficacy and safety of frontline regimens for older transplant-ineligible patients with multiple myeloma: A systematic review and meta-analysis. J Geriatr Oncol. 2020;11(8):1285-1292. doi:10.1016/j.jgo.2020.05.013

8. Larocca A, Bonello F, Gaidano G, et al. Dose/schedule-adjusted Rd-R vs continuous Rd for elderly, intermediate-fit patients with newly diagnosed multiple myeloma. Blood. 2021;137(22):3027-3036. doi:10.1182/blood.2020009507

9. Bonello F, Boccadoro M, Larocca A. Diagnostic and Therapeutic Challenges in the Management of Intermediate and Frail Elderly Multiple Myeloma Patients. Cancers (Basel). 2020;12(11):3106. Published 2020 Oct 24. doi:10.3390/cancers12113106