Each month, the Multiple Myeloma (MM) Hub will be providing content on a different educational theme. This month the MM Hub will be focusing on patient reported outcomes (PROs) and quality of life assessments (QoL). This article will introduce PROs and QoL assessments in MM, as well as set the scene for the content that will be following in the coming weeks.
Current treatment paradigm for MM
Treatment options for patients with MM are rapidly evolving, consisting currently of; immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), histone deacetylase (HDAC) inhibitors, autologous stem cell transplant (ASCT), allogeneic stem cell transplant (allo-SCT) and monoclonal antibodies. Many other novel drugs are in clinical trials, for example, chimeric antigen receptor (CAR) T-cell therapy. Usually these drugs are used in combination, with an aim of achieving a profound response to first-line therapy. However, MM is a disease characterized by frequent relapses, with patients often becoming refractory to the drugs used. Furthermore, the use of combination therapies comes with associated toxicity, and the more lines of treatment a patient receives, the more complications and treatment-related symptoms develop.1
Various factors will be considered by a physician when determining the correct course of treatment. Some of these include transplant eligibility, age, frailty, disease stage at diagnosis, comorbidities and the genetic profile of the disease, specific to each patient.1 Since patients develop more complications over time, the use of therapies have to be carefully considered, with health-related QoL (HRQoL) being a key factor in treatment decisions. The ability to predict response to treatment will also assist treatment decisions, as we move into an era where personalized medicine is becoming plausible.1
Impact of drug administration on QoL
MM is predominately a disease affecting elderly patients, with a third of patients being over the age of 75 at diagnosis.1 Patient age itself does not preclude certain treatment options, however it is a consideration for determining appropriate treatment. Treatments administered in the outpatient setting or at home are sought after, as this prevents the necessity to travel to a hospital facility which can often require long journeys. Examples of these treatment options include the IMiDs, such as lenalidomide, which are orally administered.1
Additionally, subcutaneous (SC) administration is becoming more frequently used to minimize infusion time and improve tolerability. The recent COLUMBA trial, demonstrated that SC administration of daratumumab was non-inferior to intravenous (IV) infusion. In this study, the median duration of infusion with SC daratumumab was reduced to five minutes, compared to seven hours for the first, and 4.3 hours for the second when given as an IV. Significantly, in this study, patients reported an improved experience with SC daratumumab.2
VIDEO INTERVIEW: ASCO 2019 | Highlights of the randomized phase III COLUMBA study.
Frailty scores in MM
There is a general consensus that age alone is not a predictor of response, and that frailty should be incorporated into treatment decisions. However, there is a lack of agreement over the definition of frailty in MM.1,3 .
Frailty can include:1
- Decline in functional capabilities due to disease-related symptoms
- Medical comorbidities such as high blood pressure, heart conditions and renal failure
- Cognitive impairment
- The use of other medications
It is important for physicians to agree on the definition of frailty, in order to make best-informed choices for each patient, to ensure QoL is maintained. This is significant since older, frail patients, may not experience a benefit from treatments which cause severe side effects, and potentially lead to early mortality. Novel treatments have the potential to circumvent some of the negative impact that frailty has on clinical outcome, though studies utilizing a universally accepted frailty index are required. Currently, different models are used, meaning results cannot be directly compared.3
Professor Zweegman spoke to the MM Hub about the issue of frailty in MM, which can be viewed below.
VIDEO INTERVIEW: Sonja Zweegman | EHA 2018 | The issue of frailty in MM
Patient reported outcomes (PROs)
Historically, clinical management of patients with MM has relied on observations such as response rates and physician-reported toxicities. The use of HRQoL and other PROs such as symptoms, may help better inform patient care. To enable this, it is important to develop standardized and validated measurements. The pros and cons often associated with PROs are shown in Table 1.
Table 1. Pros and cons of PROs in MM and other hematological malignancies1,5
Gain unique understanding of the patient’s individual disease and how treatment affects their life
Real-time monitoring requires more effort in daily practice. This is for the physician to maintain and review the data, as well as for patients to input their daily symptoms
Improved symptom control
Potential cost implications to healthcare providers
Improved patient-physician communication
Increased satisfaction with care and patient wellbeing
Recording of real-time information using a web-based system allows physicians to identify symptoms of concern with ease from data which would otherwise not been available or relied on patient memory
Existing PRO tools
There are many existing PRO tools including; the functional assessment of cancer therapy-multiple myeloma (FACT-MM), EORTC-QLQ-MT20, myeloma patient outcome scale (MyPOS) and the hematological malignancy – patient reported outcome measure (HM-PRO).1,4,5,9
During the Clinical Advances in Myeloma meeting held in London, UK, in January 2019, Professor Sam Salek, University of Hertfordshire, UK, presented on the topic of improving PROs. Professor Salek and colleagues developed a PRO tool, called HM-PRO, which was designed to measure the HRQoL issues (part A) and symptoms and side effects (part B).4,5
- Examples of HRQoL issues included; disease-related symptoms, insurance problems, body image issues, sexual problems, social wellbeing, impact on job and financial impact
- Examples of signs and symptoms included; anemia, chest pains, bone lesions, back pain, fever, weakness, weight loss, loss of appetite and infections
In three phases from 2014 to 2018, the HM-PRO tool was developed with key stakeholders including patients, clinicians and the pharmaceutical industry. It is now available as an app which can be downloaded onto smart phones and tablets. The app separately calculates scores for part A and B and graphically displays them to show the impact of the patient QoL and symptoms. Professor Salek recommended this be adopted into clinical trials.4,5
PROs in clinical trials
PROs have already been utilized as secondary endpoints in many randomized controlled trials, but further deployment is required to add to the evidence base, as well as the accumulation of real-world data.
Studies such as ENDEAVOUR have conducted HRQoL subgroup analyses. The ENDEAVOUR study had previously shown that carfilzomib and dexamethasone (Kd56) improved progression-free survival (PFS) compared to bortezomib and dexamethasone (Vd) in patients with relapsed/refractory MM (RRMM). The subgroup analysis showed Kd56 gave a statistically, but not clinically, significant improvement in mean HRQoL scores compared to Vd. Kd56 also significantly prolonged time to deterioration in Global Health Status (GHS) QoL, physical function, nausea/vomiting, side effects and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-Ntx).6
In the Myeloma X trial, patients received either salvage ASCT (sASCT) or nontransplantation consolidation (NCT). A subgroup analysis from this study evaluated QoL and pain in sASCT as secondary outcomes using QoL instruments. Of the 288 patients evaluated for a median follow-up of 52 months, pain interference was higher in the sASCT group than in the NCT group at six months and up to two years. Patients who received sASCT had a reduced QoL and higher impact of treatment-related adverse effects lasting for six months, and two years for pain, after which they reported better outcomes. Patients with lower adverse effects post-sASCT had a longer time to progression and OS indicating symptom management at the time of transplantation needs to be improved.7
QoL considerations in MM was also a topic discussed at the 4th World Congress on Controversies in Myeloma (COMy) meeting by Dr Rachid Baz. Dr Baz stated that data on HRQoL was limited outside clinical trials and that generally HRQoL deteriorates over time, worsening with subsequent lines of therapy. In Dr Baz’s opinion, there is strong evidence for the incorporation of HRQoL assessments in randomized controlled trials though the tools must be standardized and validated. Real-world studies of HRQoL are also warranted, to consider the financial burdens and social factors.8
Professor Shaji Kumar spoke with the MM Hub at the ESH meeting in 2018 about new end-points and design for clinical trials, explaining that using PROs may be bought into trials for MM.
VIDEO INTERVIEW: Shaji Kumar | ESH MM 2018 | New end-point and new design for clinical trials:
PROs in clinical decision making
The use of PROs and QoL information in clinical decision-making has also been discussed during recent congresses. Dr Karthik Ramasamy spoke to the MM Hub about making clinical decisions based on patient QoL at the European Society for Blood and Marrow Transplantation (EBMT) congress, Frankfurt, DE, in March 2019.
VIDEO INTERVIEW: Karthik Ramasamy | EBMT 2019 | Clinical decisions based on patient quality-of-life in MM
Disparity between clinician- and patient-reported outcomes
It has been shown in MM that physicians can underestimate the symptom-burden of their patients and that there is a lack of correlation between symptomatic adverse events (AEs) reported by physicians, and symptoms reported by patients. For example, Lene Kongsgaard Nielsen and colleagues showed that patient-reported and clinician-reported AEs were poorly correlated when completing a series of three HRQoL questionnaires during treatment with clarithromycin, bortezomib, cyclophosphamide and dexamethasone. In fact, in this study the authors concluded there was “clear underreporting of toxicities by clinicians”.9
This is significant as the understanding of efficacy and safety of a treatment is based on adherence to a treatment regimen. If patients do not adhere to therapy in order to avoid unpleasant AEs, this impacts the study conclusions. Additionally, if conclusions are drawn based on restricted or limited data, this will not translate into the real-world setting.1
Therefore, it is important to monitor the patient’s symptom burden and HRQoL, particularly in the outpatient setting, where oral therapies are increasingly utilized to promote patient independence. Using self-reported QoL measures may help identify treatment compliance issues, allowing earlier intervention.1
Examples of studies on QoL in MM
In a study by Christina Ramsenthaler and colleagues, published in BMC Cancer in 2016, it was shown that patients with MM have a high symptom burden and low HRQoL in both early and advanced stages of disease. The mean number of symptoms per patient (N= 557) was 7.2 out of a potential 15, the most common of which were pain (72%), fatigue (88%) and breathlessness (61%). Patients with RRMM had the highest mean number of symptoms. Factors associated with high palliative care concerns were identified to be; a high symptom level, pain, anxiety, low physical function, a younger age, and advanced stage of disease. The authors of this study concluded that the identification of patients who require supportive care should be done using PROs and be complementary to traditional biomarker assessment.10
In July 2019, Professor Graham Jackson and colleagues, published the results of an analysis of productivity losses in patients with NDMM following ASCT in the European Journal of Haematology. The study analyzed patients prior to diagnosis and post-ASCT to evaluate the impact of transplant on productivity, employment and work. It subsequently analyzed whether maintenance therapy with lenalidomide could reduce this productivity loss, as lenalidomide maintenance has previously been shown to increase overall survival (OS), PFS and HRQoL.11
- Patients (N= 115) were recruited from five European countries (UK, France, Germany, Italy and Spain, EU5) and asked to complete an online survey
- 76.5% of patients were economically active at diagnosis
- 39.1% were economically active post-ASCT
- Proportion of patients in full-time employment: 46% (at diagnosis) vs 17% (post-ASCT)
- Productivity loss was highest in patients aged 50–65 years compared to those < 50 years old
- Most productivity losses observed were due to patients retiring or not returning to work
- Estimated productivity loss per ASCT patient (over a 20-year period): €290,601
- Maintenance with lenalidomide reduced this loss by ~10%
This study evaluated patient-reported survey data. Patients prioritized a desire to lead an active life over the financial aspect of working, and 80% of overall productivity loss was contributed to an inability to return to work due to a lack of fitness to carry out routine tasks.11
In summary, most patients highlighted that returning to work was a factor affecting their QoL, though unfortunately most are unable to, post-ASCT. Extending remission periods and encouraging engagement in a productive life can have a positive impact on the patient as well as the wider society.11
Studies such as that by Graham Jackson and colleagues highlight the need to support patients with NDMM, post-ASCT, who wish to return to employment, as well as noting the impact of ASCT on productivity.
There are many different factors to consider when determining the appropriate treatment for a patient with MM. In addition to the current standard-of-care treatments authorized within each country, physicians must consider whether a clinical trial involving a novel therapy or new combination is suitable, and combine this with information about the patient’s cytogenetics and baseline characteristics. Since myeloma is a disease characterized by frequent relapses with a long treatment pathway, maintaining patients QoL throughout must be a significant consideration within complex treatment decision-making. Using PROs in clinical trials will enable pharmaceutical companies and physicians to develop treatments that maintain QoL, leading to better adherence and ultimately, outcomes and experiences.