Chapter 4 – Treatment of elderly patients with myeloma

Contributors: Eileen M Boyle, Charline Legrand, Hélène Demarquette, Stéphanie Guidez, Charles Herbaux, Xavier Leleu, and Thierry Facon

3 – Biological and clinical features

Cytogenetics and biology

The genetic make-up of myeloma is vastly similar in terms of cytogenetic abnormalities and mutational spectrum among the young and the elderly (Walker et al, in press). Interestingly, the incidence of t(4;14) and del(13q) decreases with age [7] whereas del(17p) is remarkably stable. From a mutational perspective, the mutational spectrum does not vary between young and older patients, but a mutational signature related to age according to Alexandrov et al [8] may be found in myeloma tumor samples [9].

Clinical features

Besides these slight biological variations, clinical differences ought to be taken into consideration when treating elderly patients. Age and the human aging process it reflects are an essential component but they do not solely define this population [4,5,7,8,10]. In order to account for the heterogeneity of the elderly population, age should be combined with notions such as frailty and comorbidity, which can also predict outcome. Frailty is a distinct clinically recognized phenotype but no single sign or symptom is sufficient to define it. Usually, it requires at least three core elements from the following list: weakness, poor endurance, weight loss, low physical activity, slow gait, and speed. Specific indexes have been developed (Table 4.1) to measure and compare frailty between patients and have been used to predict poor outcomes in oncology [8,10]. The human aging processes is associated with a decrease in physiologic reserves, and a change in body composition (decrease in muscle mass, increase in fat, and increase in intracellular water) and age-related changes in organ function. These elements affect metabolism, distribution, pharmacokinetics and pharmacodynamics of myeloma drugs, and often account for the poor tolerability of the treatment [11].

The second important component we ought to take into account is the presence of comorbidities or treatment-requiring associated diseases. Among the frequently used scales to quantify comorbidities, the Charlson scale [11] was often perceived as too complicated for routine clinical practice [12] and has been replaced by the user friendly, well-validated, Cumulative Illness Rating Scale (CIRS) index [10]. Comorbidity, and the subsequent polymedication, may be associated with drug interactions and modified toxicity profiles [11]. Disability is also an important component to keep in mind when assessing geriatric patients. This can include physical and mental impairments and, regardless of its causes, is associated with a higher mortality risk [13].

Table 4.1 Frailty indices: adapted from the European myeloma network guidelines.

Reproduced with permission from © the American Society of Hematology, 2011. All rights reserved. Palumbo et al [14].

More recently, the IMWG introduced a simplified geriatric assessment that combines age, comorbidities and disability. In addition to age, three tools are used including the Katz Activity of Daily Living (ADL), the Lawton Instrumental Activity of Daily Living (IADL), and the Charlson Comorbidity Index (CCI). The additive scoring system (range 0–5) based on these variables, stratifies patients into three distinct risk groups for overall survival: fit (score=0), intermediate (score=1) and frail (score ≥2) (see Figure 4.1). The score has demonstrated the ability to predict survival and toxicity with the highest risk group associated with an increased risk of death, progression, treatment discontinuation and non-hematologic toxicities [15]. It is therefore predicted to become a useful tool in determining the feasibility of treatment regimens and appropriate dose reductions. Nonetheless, more validation is needed in a real-world setting.

Figure 4.1. Framework for the definition of frailty status in elderly patients with multiple myeloma.

ADL, activities of daily living; CCI, Charlson Comorbidity Index; IADL, Instrumental Activities of Daily Living. Adapted from Larocca and Palumbo 2016 [16].