Towards the integration of patient-reported outcomes into the global clinical management of multiple myeloma

KEYWORDS:

• Multiple myeloma
• quality of life
• patient-reported outcomes
• decision-making

1. Introduction

Although multiple myeloma (MM) remains an incurable disease, the treatment landscape for the management of MM has substantially evolved over the past decade. Indeed, an extraordinary and ever-growing medical armamentarium is constantly being implemented by more effective targeted drugs, which now include immunomodulatory drugs, proteasome inhibitors, histone deacetylase inhibitors, and monoclonal antibodies [1]. In addition, one should consider that oral therapies will increasingly be used, therefore adding other important challenges with regard to patients’ management. Indeed, several highly effective drugs are also available as oral agents and their use can improve patient’s management, although they are typically more expensive than parenteral compounds [1,2]. In addition, subcutaneous administrations are also increasingly compared to intravenous (IV) long infusions, representing this route another good option to facilitate patient’s management. Therefore, compared to the recent past, a wide range of treatment agents is now available and several other therapeutic approaches, such as chimeric antigen receptor T (CAR-T) cell therapy and Immune checkpoint inhibitors [1,2], are under development. As a result of the introduction of novel agents, the clinical outcome of MM has significantly improved and, for many of patients, the disease has turned into a long-term chronic condition characterized by clinical remissions alternated with relapses [1,2]. Given that MM typically affects elderly patients with approximately one-third of patients being older than 75 years at the time of diagnosis, the incidence is rising due to population aging [3]. Therefore, their frailty, which may include the decline in functional capacities due to disease-related symptoms as well as to medical comorbidities, cognitive impairment, and polypharmacy, should be carefully considered to best evaluate potential implications for treatment discontinuation, therapeutic efficacy, and health-related quality of life (HRQOL) impact [3–6]. During their disease history, many MM patients may receive multiple lines of therapies and live with their illness for many years experiencing disease complications as well as treatment‐related symptoms [1,2,5]. Briefly, patients with newly diagnosed MM (NDMM), according to their fitness, should receive a frailty-oriented treatment [3], which often consist of a combination of drugs with specific toxicity profiles [1–6]. Therefore, effective treatment options in MM can help maintain HRQOL by influencing treatment response levels and delaying disease progression [1,3]. In responsive NDMM patients, the potential eligibility for autologous stem cell transplant (ASCT) is the most important driver for appropriate decision-making. In turn, transplanted patients are currently candidates for long-term maintenance therapy with oral immunomodulators, such as lenalidomide. According to disease phases and dominating clinical features, other MM management settings include relapsed/refractory MM (RRMM) patients, and those with more advanced disease, often requiring palliative care measures. Therefore, owing to the variability of the disease course, accurate identification of life expectancy, and likelihood of diease progression have historically been a major issue for clinical decision-making. Clinical management of MM patients has traditionally been driven by clinical criteria, such as clinical response, and physician-reported toxicities [7,8]. Therefore, in this increasingly complex scenario, the assessment of patient-reported HRQOL or other patient-reported outcomes (PROs), such as symptoms, could provide additional information to more robustly inform patient care [9–11]. Indeed, measuring PROs by using standardized and validated tools is the only way to get the unique patients’ view on the impact of the disease and therapy on his/her own life [10,11]. Examples of MM disease-specific PRO tools include the Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM) [9] and the EORTC-QLQ-MY20 [12]. Notably, PROs have typically been used in a randomized controlled trial (RCTs) as secondary endpoints and, in many cases, have provided novel information that have helped the scientific community to more thoroughly understand overall treatment effectiveness of the drug being tested. Also in particularly challenging settings, such as those including RRMM patients, PROs have contributed to a better understanding of the impact of drugs from the patients’ perspective. To illustrate, a recently published large multicenter study, which randomly assigned patients to either salvage autologous stem-cell transplantations (sASCT) or nontransplantation consolidation (NTC), has shown that collecting PRO data is feasible also in such difficult RCT settings (i.e. enrolling patients from several centers and administering questionnaire to frail patients) and can provide important information to enhance informed treatment-decisions [13]. Indeed, clinical results of this trial previously noted that those patients treated with sASCT had better clinical outcomes including overall survival (OS) compared to patients treated with NTC [14]. However, effects of sASCT on patients’ HRQOL were largely unknown. Therefore, a comprehensive PRO data analysis was performed indicating short-lasting worsening of some key HRQOL domains, including pain, for sASCT compared to NCT. Furthermore, it was shown that patients receiving sASCT had higher pain interference for up to 2 years after randomization. Notably, despite these short-term negative HRQOL effects, differences favoring NCT tended to disappear over the long-term period, and also favored sASCT patients in some key HRQOL domains [13]. Unfortunately, the use of PRO assessment in real-life studies has been less common but still informative. For example, a recent study in RRMM patients showed that HRQOL decreased significantly with treatment lines [4]. This evidence is particularly relevant as there is paucity of evidence-based information on PROs in RRMM patients [15].

2. Implementing patient-reported outcomes in clinical practice in the era of oral MM therapies: implications for symptom management and adherence to therapy

As a result of the remarkable advances of clinical research in MM over the last two decades, treatment decision-making and patient’s management has substantially grown in complexity. For example, appropriate management of AEs is crucial in clinical practice and prompt recognition of them by the treating physician is of crucial importance. Indeed, considering the chronic nature of MM treatments, even low-grade AEs might potentially interfere with patient’s daily living and negatively impact overall wellbeing and HRQOL [11]. Previous studies in cancer patients have shown that physicians often underestimate symptom burden of their patients [16]; and poor correlations between symptomatic AEs reported by physicians and symptoms reported by patients have also been documented in MM [17]. What are the possible implications of this ‘mismatch’ between the physicians’ perception and the real treatment burden experienced by patients? An immediate one, for example, might be that of assuming that patients are fully adherent to therapy, while in fact, they are not as they tend to skip therapy to avoid bothersome AEs. Considering the importance of adhering to the prescribed MM treatment schedule in order to maximize drug effectiveness, it becomes critical to improve our ability to better monitor patient’s symptom burden and HRQOL. While this aspect has not been a key concern in the past, it now becomes an additional challenge that we need to consider due to the increasing use of oral therapies. Inclusion of a more systematic assessment of the patient’s perspective into routine care, through the use of validated and standardized patient’s self-reported HRQOL measures, can be instrumental to more accurately monitor the treatment burden and potentially identify patients at heightened risk of poor medication-taking behavior. It is important that MM patients who take oral therapies at home, report symptoms before they become difficult to manage [18]. This is particularly true for the nonhematologic toxicities (i.e. symptomatic toxicities), which are best known by the patients themselves. There is a wealth of empirical data indicating that systematic use of PRO measures in routine practice is feasible and it is associated with several benefits, including improved symptom control and patient-physician communication, as well as enhanced satisfaction with care and patient outcomes and wellbeing [11,19]. Such PRO monitoring can be implemented in several ways and, a number of web-based PRO systems are already available and used in various oncology clinics [20]. These systems typically provide real-time, graphical feedback of PRO scorings, which can be used by physicians to focus on key symptoms in need of special attention, during the consultation. To conclude, implementation of a more systematic assessment of PROs into clinical practice can be critical to more robustly inform patient care and facilitate the transition to a more personalized treatment approach. This can be of particular importance in the current MM clinical arena, given that a large number of drugs are now part of the physicians’ armamentarium.

Declaration of interest

F Efficace has acted as consultant for Bristol-Myers Squibb, Amgen, Orsenix, Incyte and Takeda outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.