The relative importance of factors predicting outcome for myeloma patients at different ages: results from 3894 patients in the Myeloma XI trial

Abstract

Disease factors such as tumor burden and molecular risk affect myeloma patient outcomes as well as patient factors that impact the capacity to deliver treatment. How the relative importance of these factors changes with patient age has not previously been investigated comprehensively. We analyzed data from 3894 patients of all ages uniformly treated in a large clinical trial of myeloma patients, Myeloma XI. Even with novel therapeutic approaches progression-free survival (PFS) and overall survival (OS) are affected by age with a stepwise reduction in PFS and OS with each decade increase. Renal function deteriorated with increasing age whilst the frequency of t(4;14) and del(17p) decreased and gain(1q) increased. The relative contribution of performance status, international staging score and molecular risk to progression-free and overall survival varied by age group. Molecular events have a larger effect on outcome in younger patients with their relative contribution diminishing in the elderly. Performance status is important for patient outcome at all ages suggesting that physical frailty may be a more important predictor of outcome than age itself. Significant differences in the factors driving patient outcomes at different ages are important to consider as we design disease segmentation strategies to deliver personalized treatment approaches.

Defining the vulnerable patient with myeloma—a frailty position paper of the European Myeloma Network

“…For example, similar outcomes have been reported in the >75 years old patient cohort in both the POLLUX and CASTOR trials [10]. Treatment strategies for patients deemed TNE have evolved and it is clear that improvements in survival have been less impressive in this group of patients [7,11]. This is probably an under-estimation, in part, due to an underrepresentation of less fit patients in clinical trials due to strict entry criteria (see below) and a reflection of real-world practice where physicians may be less confident about delivering full dosing and delivery schedules in the more frail patient.…”

“…In MM in patients deemed to be TNE there is considerable heterogeneity, not only in age but also the complex interplay of age, physical function, cognitive function and comorbidity. Furthermore, performance score (PS) and the ISS has been shown to be less able to discern these key sub-groups in the TNE population and predict their response to therapy and survivorship [7,26]. A functional or GA offers the possible advantage of guiding therapeutic decisions with the potential to account for treatment compatibility, drug-induced side effects and mortality [27,28].…”

“…As a consequence patients ineligible for RCTs demonstrated more advanced disease (Connect MM Registry ISS III 22.1% in RCT eligible versus 40.1% in RCT ineligible; p < 0.001). NCRI Myeloma XI, the largest upfront trial in newly diagnosed MM, had a median age of 74 in the TNE cohort though only 13.2% were older than 80 years compared with the population rate of MM in the UK where 54.8% are older than 80 years of age [7]. As such it is clear that any clinical scoring system or biomarker, whether prognostic or predictive needs to be evaluated in a realworld population if the true impact on everyday clinical practice is to be measured [20,33,35,42,70].…”

“…However, the impact of these therapies has been less marked in the older/less fit transplant non-eligible (TNE) population, particularly those over the age of 75 years [6]. These patients do not have a greater incidence of molecularly high-risk disease and so these differences are likely to be accounted for by differences in patient physiology, increased treatment-related toxicity limiting delivery of effective therapy and less effective, rigorous anti-myeloma treatment being given (undertreatment) [7]. Life expectancy is extremely variable in the same age group, thus suggesting that not only chronological age is important but also the health status of the patient [8].…”

Maintenance therapy in transplant ineligible adults with newly‐diagnosed multiple myeloma: A systematic review and meta‐analysis

“…Interestingly, even the OS benefit in the transplant setting was heterogenous and less pronounced for patients older than age 60 years 5 . Given that the transplant ineligible population is older, it was not surprising that we were unable to show an OS benefit in the transplant ineligible setting as OS in this population is known to be much more affected by a number of competing factors including co‐morbidities and functional status compared to younger patients 26 …”