A frailty scoring system created by the International Myeloma Working Group (IMWG)—the research arm of the International Myeloma Foundation, made up of approximately 160 myeloma researchers around the world—appears to make possible better assessment of the risk of mortality and toxicity in elderly patients with newly diagnosed multiple myeloma.
The research team, led by Antonio Palumbo, MD, Chief of the Myeloma Unit at the University of Torino in Italy, evaluated pooled data from three prospective trials on 869 newly diagnosed elderly patients. A geriatric assessment was performed in each patient at the time of diagnosis and a scoring system of 0 to 5 was used based on age, comorbidities, and cognitive condition. The findings were published in the March 26 issue of Blood (2015;125:2068-2074).
Patients were classified into three groups:
- Fit (score of 1, 39 percent of patients);
- Intermediate (score of 2, 31 percent of patients); and
- Frail (score lower than 2, 30 percent of patients).
With a median 18 months of follow-up, the three-year overall survival rates were 84 percent in fit patients, 76 percent in the intermediate group, and 57 percent in frail individuals. The cumulative incidence of grade 3 or higher nonhematologic adverse events at 12 months was 22.2 percent in fit patients, 26.4 percent in the intermediate-fitness category, and 34.0 percent in frail subjects.
The cumulative incidence of treatment discontinuation at one year was 16.5 percent for fit subjects, 20.8 percent for those in the intermediate-fitness category, and 31.2 percent in frail patients. The frailty scores were still associated with overall survival regardless of staging and type of treatment regimen, the study showed.
Three Instead of Two Categories
“Until now we had young and elderly; now we have young, elderly fit, and elderly frail—basically three categories instead of two,” Palumbo said in an interview.
“Age and comorbidities are not always the first issues considered before treatment. This should be the case, but it is not always. More education on this issue is very badly needed. To deliver a full dose of chemotherapy in a frail patient exposes them to a significant greater risk of comorbidities, and this often results in discontinuation of therapy.”
Because the system better predicted mortality, toxicity, and the likelihood of treatment discontinuation, the IMWG B, which sponsored the study, proposed using frailty scoring system in designing future clinical trials of blood cancer treatments, Palumbo noted.
“Simply relying on age, physical performance, and a doctor's clinical judgment are insufficient to properly assess risk in elderly patients who are diagnosed with melanoma. This assessment tool is a more sensitive predictor of clinical outcomes, and the proposed score may be adopted as a valid new standard to evaluate patient frailty.”
The researchers found that even subjects in the intermediate fitness category experienced a slightly higher risk of grade 3 or higher non-hematologic adverse events, while the risk in frail patients was significantly greater. Grade 3 or higher non-hematologic adverse events occurred in 18 percent of fit subjects, 22 percent in the intermediate patients, and 30 percent of frail individuals.
Over the length of the study, the researchers reported that 17 percent of fit patients discontinued drug treatment for any cause, excluding death or disease progression, while 22 percent of the intermediate category discontinued treatment as did 25 percent of the frail subjects.
“The relationship between fitness and discontinuation of treatment is difficult to clearly define,” Palumbo said. “Frailty and discontinuation are major factors that reduce outcome, and are both equally important. But frailty appears to increase toxicity, and that is a major cause of therapy discontinuation.”
Combining frailty scores with the International Staging System (ISS), the three-year overall survival rate was 55 percent in the frail-ISS 3 patients but 94 percent for fit-ISS 1 individuals, the researchers found.
“The combination of these two independent parameters significantly improved the prognostic value of the single ones. This is therefore an important strategy in the future for predicting outcome. The scoring system could be used in everyday clinical practice as well as in the context of research to ensure an adequate representation of elderly patients and to allow more precise cross-trial comparisons,” the authors noted.
Palumbo said that the major limitation of the findings was that the study was retrospective—unfortunately, though, it is difficult to perform prospective studies in this setting, and the group is not planning any additional studies of the scoring system at this time.
At Ohio State University's Wexner Medical Center, Ashley Rosko, PhD, Assistant Professor in the Division of Hematology is hoping to incorporate biomarkers into a fitness staging prognosis.
She was awarded a $150,000 new investigator grant from the National Comprehensive Cancer Network last year to conduct a study on comprehensive geriatric assessment and biomarkers of aging investigation among seniors with myeloma.
She is now conducting a pilot trial studying an electronic comprehensive geriatric assessment to measure fitness in pre-autologous hematopoietic stem cell transplantation (AHSCT) in older myeloma patients and determine the ability of molecular biomarkers, especially p16 expression in peripheral blood T- lymphocytes, to measure patient fitness and predict return to function after AHSCT.
She noted in an interview that the researchers have enrolled some 80 patients to date with a target of 100 subjects, and the hope is to present preliminary findings at the American Society of Hematology Annual Meeting in December.
“With the aging of the population, the need for such research has become more pressing,” Rosko said. “We are looking at multiple occult assessment factors. Generally these patients' frailty is determined by their gait, how well they can rise from a chair, and cognitive factors, but geriatric assessment is more than just those factors.
“In addition to cognitive assessment and these issues, we also inquire about social support, nutrition, and a history of falling. It is very important to know how these patients are functioning at home and how they were doing before their cancer diagnosis.”
She commended the Italian study for including such a large number of subjects, which is difficult. “We are learning that functional and cognitive performance assessment is not enough. All of the patients included in the analysis were from clinical trials, and with trials the inclusion criteria is pretty stringent. But Dr. Palumbo and his colleagues were able to stratify them. The bottom line is that we need to redesign our approach to assessing such patients.
“In the studies used in this paper much of the data was subjective and came from self-reporting of things like gait, cognition, and balance. Using objective biomarkers might be a better tool and should be explored further.”
Molecular markers like p16 have never been explored before in these older multiple myeloma patients, with longer follow-up of toxicity, disease progression, and death.
In an accompanying editorial (Blood 2015;125:2014-2015), Ulf-Henrik Mellqvist, MD, PhD, Chairman of the Nordic Myeloma Study Group and a researcher in the Hematology Section at Gothenburg University and Sahlgrenska University Hospital in Sweden, said the stratification method reported by Palumbo et al might be a useful tool in identifying both it and frail elderly multiple myeloma patients: “Like most malignancies, multiple myeloma mainly affects elderly patients. Even so, in daily clinical practice, we usually consider only chronological age. It is quite obvious, however, that there is a huge difference between a 70-year-old fit patient and a frail patient above the age of 80.”
The inferior survival rates found in older frail patients was most likely due to a greater frequency of treatment discontinuation and nonhematologic adverse events, and although a number of assessment and staging systems have been developed, not all have shown benefits, Mellqvist said.
“But so far they have not been able to provide information for adjusting the treatment of the individual patient. In this study, the authors show that their new system could produce information not possible to obtain by using standard performance status, ISS, or even biological data from chromosomal analyses, which we normally regard as very important prognostic tools.”
The study is also important because it has the potential to help guide individual treatment regimens, and by identifying frail patients, it could help clinicians choose well-tolerated, low-toxicity drug combinations and avoid harmful treatment regimens, Mellqvist wrote.
“Another potential important issue for a new robust frailty scoring system could be that elderly patients found fit could benefit from more intense treatment.”