HOW TO TREAT UNFIT AND FRAIL PATIENTS

Therapeutic options have greatly expanded over recent years defining new standards of care in multiple myeloma (MM). However, MM is a heterogeneous disease as are the patients it affects. As the median age of MM at presentation is 70 years, treating physicians are faced with the quandary of how to efficiently identify frail individuals that may have more difficulty tolerating and recovering from systemic therapy, thus being in need of treatment delivery modifications. Recently developed clinical scoring systems which are able to delineate patients into fit, unfit & frail groupings, with respective differences in PFS and OS in clinical trials have been highlighted. To date these have been proven to be prognostic biomarkers yet not evidence exists as to their potential as predictive biomarkers and thus used in the clinic to direct treatment decisions. Consequentially, such identified limitation have led to a study in the front-line setting using frailty scoring to prospectively adapt therapy (UKMRA Myeloma XIV trial). Dose and delivery modifications may be pertinent to patients with altered performance if we are to attain similar outcomes as with younger patients in the current era of novel agent combinations. The potential exists for improving performance (senolytics, exercise, nutrition) as well as how we measure performance more accurately through establishing digital phenotypes.

Such clinical frailty scores may allow for better prediction of toxicity but there is a need for the development of additional, biological-based tools to reflect the processes of accelerated aging and how they impact on tolerance of cancer treatment and survivorship. Identifying specific biologic determinants of frailty may allow physicians to become even more adept at identifying patients at risk of excessive toxicity and provide the opportunity to target these processes therapeutically to help improve tolerability, quality of life and survival outcomes for older patients with cancer. Host response biology (HRB), is the measurable pathophysiological processes resulting from the impact of disease and accelerated aging on an individual’s biological function. Biomarkers of HRB can include end-organ damage parameters, clinical scoring systems of fitness, immune system quantitation (immunosenescence) and serial markers of age-related inflammation (inflammaging). Less fit patients represent a substantial proportion of newly diagnosed patients requiring treatment. Whilst age does not necessarily equate to fitness to tolerate therapy nonetheless age-related inflammation is perhaps the most important physiologic correlate of the age-related frailty syndrome.

There is a need to design clinical trial research going forward, cognisant of a number of disease and patient related determinants, realising the mantra that “one size doesn’t fit all” which will inevitably allow us to deliver Better Research, Better Impact.