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  1. Spotlight on CDER Science

Using Patient-Reported Outcomes to Measure Frailty in Patients with Multiple Myeloma

Frailty is an aging-related syndrome of cumulative physical and physiological decline, which can include symptoms such as weakness and fatigue, greater medical complications, and lower tolerance for medical treatments.

In patients with oncologic diseases, frailty increases the risk of side effects, treatment discontinuation, disease progression, hospitalization, and death. For these reasons, it is important to assess patients’ frailty to help make informed treatment decisions. Evidence shows that considering patients’ frailty levels while selecting treatments, adjusting doses, and providing supportive care may help reduce side effects and improve patients’ ability to tolerate medications.

Multiple assessments, indices, phenotypes (criteria of observable characteristics in an individual), and questionnaires have been developed to detect frailty and guide treatment decisions in older patients with cancer. One well-known tool is the Fried Frailty Phenotype1, which assesses frailty through five measures: unintentional weight loss, weakness or poor handgrip strength, self-reported exhaustion, slow walking speed, and low physical activity. However, these frailty assessments can require additional time and resources to conduct, especially if clinician evaluations are necessary.

Frailty measures that use patient self-reports called “patient-reported outcomes” (PROs) can provide scientific information on a patient’s experience coming directly from patients. PROs can offer valuable information about a patient’s own health, quality of life, and functional capabilities, and have been gaining traction in health care.

FDA’s Recent Research

FDA and outside researchers explored whether patient responses to select questions within a commonly used questionnaire to assess quality of life in patients with cancer, the European Organization for Research and Treatment of Cancer Quality of Life 30-item Questionnaire (EORTC QLQ-C30),2 could be used as a proxy (substitute) for the Fried Frailty Phenotype to assess frailty in patients with multiple myeloma. Essentially, these researchers were aiming to create a Patient-Reported Frailty Phenotype that could retroactively detect frailty using previously reported patient responses.

First, researchers scanned FDA databases to identify phase III randomized clinical trials submitted for regulatory review between 2010 and 2021 for multiple myeloma treatments. Altogether, nine trials were included. Researchers limited analysis to patients with relapsed (recurring)/refractory (unresponsive to treatment) disease who had fully completed the EORTC QLQ-C30 questionnaire at baseline.

Researchers then selected questionnaire items that measured the same or similar concepts to each Fried Frailty criterion to create a five-item Patient-Reported Frailty Phenotype. For example, researchers considered the questionnaire item “Have you felt weak?” as a proxy for the Fried Frailty criterion of “weakness,” which is generally measured by grip strength.3

Then, researchers categorized each questionnaire response as either “absent” or “present.” A questionnaire response of “Not at all” or “A little” meant “absent” whereas “Quite a bit” or “Very much” in the questionnaire meant “present.” Researchers gave “absent” a numerical value of 0 and “present” a value of 1. Researchers totaled the responses to the five questions and identified patients as fit (not frail, score of 0), pre-frail (score of 1 or 2), or frail (score of 3 or higher).

Patient-Reported Frailty Phenotype (PRFP)

Original Fried Phenotype of Frailty Criteria

Score (0 or 1)

EORTC QLQ-C30 Candidate Item for PRFP

Unintentional weight loss (minimum of 10 pounds or ≥ 5% of body weight within the past year)

0 or 1

Have you lacked appetite?

Exhaustion (self-reported)

0 or 1

Did you need to rest?

Weakness (typically measured by grip strength)

0 or 1

Have you felt weak?

Slowness (typically measured by observing gait speed)

0 or 1

Do you have any trouble taking a short walk outside of the house?

Low physical activity

0 or 1

Were you limited in doing either your work or other daily activities?

Summed score: 0=fit; 1 or 2=pre-frail; ≥ 3=frail
EORTC QLQ-C30 item responses were grouped as: “not at all”/ “a little” (absent)=0; “quite a bit” / “very much” (present)=1
Table is modified from the one included in the journal article.3

Study Results and Conclusions

Out of 5,272 patients, 4,928 patients (93%) completed the questionnaire at baseline and met inclusion/exclusion criteria. The median (midpoint) patient age was 65 years. The majority (82%) of patients were white and over half (55%) were male.

From using the Patient-Reported Frailty Phenotype, researchers identified 2,729 fit (55.4%), 1,209 pre-frail (24.5%), and 990 frail (20.1%) patients of the total 4,982. These findings were in line with a prior prospective study of patients with relapsed/refractory multiple myeloma, as determined by the International Myeloma Working Group frailty index. Researchers’ statistical analysis showed that the questions were well-correlated with one another, and that there was adequate internal consistency reliability (all questions were measuring the same thing) and structural validity (the test measured the concept it was designed to evaluate).2

Researchers found that frailty, as detected by Patient-Reported Frailty Phenotype, was associated with patients’ comorbidities (the presence of other conditions), mobility, self-care, and engagement in usual activities. Frail patients, for example, were far more likely to report problems with mobility (88% of frail vs. 69% of pre-frail vs. 31% of fit patients), self-care (54% of frail vs. 28% of pre-frail vs. 7% of fit patients), and engagement in usual activities (93% of frail vs. 76% of pre-frail vs. 33% of fit patients). On the other hand, there was a weak association between frailty and age (3.4% of frail patients were older than 80 years old while 3.5% of pre-frail patients were older than 80 and 3% of fit patients were older than 80).

The Role of Patients and Study Limitations

To researchers’ knowledge, this is one of the first studies to research a fully patient-reported frailty model in the context of multiple myeloma. Given patients’ first-hand experience with the disease, they are often able to self-report frailty symptoms. However, this type of scientific information is often underutilized when measuring frailty in oncology. Multiple studies in the general non-cancer older adult population have shown the value of patient-reported frailty measures.

While this study showed some potential in using PRO measures to detect frailty, it was a “proof-of-concept”— a study to test the idea of developing a patient-reported phenotype using pre-existing data. Creating a more validated questionnaire would likely require more extensive feedback from patients and experts in different scientific disciplines.

Further research is necessary to assess the association between frailty, as measured by Patient-Reported Frailty Phenotype, and clinical outcomes in multiple myeloma, and to see how this phenotype compares with other frailty measures. However, given the findings in the study, researchers believe there may more opportunities to use patient-reported data to detect frailty in other oncology settings.

1 Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. The Journals of Gerontology, Series A, Biological Sciences and Medical Sciences. 2001 Mar;56(3):M146- 56.
2 EORTC Quality of Life. Questionnaire: Quality of Life of Cancer Patients. Accessed June 30, 2023.
3 Murugappan MN, King-Kallimanls BL, Bhatnagar V, et al. Measuring frailty using patient-reported outcomes (PRO) data: A feasibility study in patients with multiple myeloma. Quality of Life Research. 2023 Mar; 1-12.

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