Multiple myeloma (MM) is an incurable hematologic malignancy diagnosed primarily in older adults. As the population ages, myeloma incidence is expected to increase at a higher rate than many other malignancies. 1 Approved chemotherapy and targeted regimens for older adults with MM are numerous and exhibit distinct toxicities. The physiological heterogeneity of older adults makes it challenging for physicians to identify the most effective, yet best tolerated regimen, for each MM patient. As such, use of a two-drug regimen, three-drug regimen, or intensive autologous hematopoietic stem cell transplant (AHSCT) is often subjective. Consequently, AHSCT eligibility is subjectively applied and more objective measures are warranted to better understand health status in older adults. We believe that objective markers of physiological age will improve treatment stratification and will be an additional tool in understanding how treatment and transplant have an impact on health status.

The molecular biomarker, p16INK4a (p16) is an established marker of systemic cellular senescence associated with physiological aging. p16 expression increases~ 16-fold over an individualLs lifetime and can be readily measured in peripheral blood T-lymphocytes (PBTLs). 2 p16 originates from the INK4/ARF locus on human chromosome 9p21 and belongs to the INK4 family of cyclin-dependent kinase inhibitors (CDKis). These CDKis prevent cell cycle progression into S-phase by blocking phosphorylation of the retinoblastoma tumor suppressor by CDK4/6. 3 On a cellular level, p16 expression increases with stress (for example, DNA-damaging stimuli, telomere erosion and oncogene expression) and, with prolonged induction, can promote an irreversible cell cycle arrest termed ‘cellular senescence. L In humans, p16 rises exponentially with chronologic age and this rate of increase is further accelerated by physical inactivity, tobacco use, chronic HIV infection and cytotoxic chemotherapy. 2, 4 The regulation of p16 expression is also linked to age-related conditions (that is, cardiovascular disease, diabetes and decreased physical function) through single-nucleotide polymorphisms located near the INK4/ARF locus. 5-7 To date, p16 expression has not been examined as a surrogate for biologic age in MM, a disease where treatment stratification is often based on chronologic age. We hypothesized that p16 levels, a marker of cellular senescence in T cells, would impart knowledge of a patientLs biological age pre-and post treatment, thus improving future therapeutic decision-making and patient outcome. We performed a pilot study to preliminarily determine the effects of therapy and/or intensive transplant (AHSCT) on biological aging using p16 levels in PBTL as a surrogate marker. Fifty-two peripheral blood samples were collected for evaluation divided into three cohorts; healthy control (n= 17), newly diagnosed (ND) MM (n= 11) and relapsed refractory (RR) MM (n= 24). Median age and ranges for healthy control, ND MM and RR MM were 60 (range 35-82), 70 (range 51-84) and 61 (range 40-70), respectively. Complete clinical data were available for 19 of 24 RR MM patients and 11 ND MM patients. RR MM patients were mostly of early stage, who underwent AHSCT (n= 23) and median two lines of chemotherapy