Multiple myeloma (MM) is an incurable, relapsing disease that is generally diagnosed in elderly individuals; median age at diagnosis is 72 years for men and 74 years for women [1
]. In recent years, mortality rates in MM have improved significantly as a result of advances in treatment [4
]. The aim of treatment has therefore shifted from purely palliative therapy to the early use of potent treatments to prolong disease control and improve overall survival (OS) [5
The World Health Organization defines quality of life (QoL) as “an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns” [9
]. Health-related QoL (HRQoL) can be additionally defined as the functional effect of a medical condition and its consequent therapy upon a patient [10
]. Patients with MM often experience substantial adverse effects on HRQoL, including pain, fatigue, and breathlessness, as well as impaired physical functioning [11
]. Furthermore, treatment-related toxicity can also negatively affect patients’ HRQoL [14
]. During treatment, HRQoL is generally maintained at baseline levels or declines, although improvements in some HRQoL domains may be seen [15
]. As a result, QoL has become an important determinant of therapy, with some physicians and patients choosing to optimize QoL at the cost of prolonged survival [20
]. QoL is also a central component of health technology and cost-effectiveness assessment [21
]. Incorporation of QoL endpoints in clinical trials is therefore essential to allow better clinical decision-making in patients with MM [22
], including those with relapsed/refractory (RR) MM.
Carfilzomib is an epoxyketone proteasome inhibitor that binds selectively and irreversibly to the constitutive proteasome and immunoproteasome. In the phase III ASPIRE and ENDEAVOR trials, carfilzomib-based therapy was associated with significantly prolonged progression-free survival (PFS) and OS compared with controls [5
]. Based on these two studies, carfilzomib is licensed in Europe and the USA in combination with either lenalidomide and dexamethasone or dexamethasone alone for the treatment of adults with RRMM who have received at least one prior therapy [25
]. Furthermore, the European Summary of Product Characteristics notes the benefits of carfilzomib on HRQoL as reported in the ASPIRE and ENDEAVOR studies. In the USA, carfilzomib is also licensed as monotherapy in patients with RRMM who have received one or more lines of therapy [26
Daratumumab is a monoclonal antibody specific for CD38, which is overexpressed in hematological malignancies such as MM [27
]. The phase III CASTOR and POLLUX trials of combinations including daratumumab showed significantly prolonged PFS versus controls [28
]. As a result, daratumumab is licensed in Europe as monotherapy for the treatment of adults with RRMM whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have progressed while receiving their most recent therapy. It is also licensed in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone for the treatment of adults with MM who have received at least one prior therapy [30
]. In the USA, daratumumab is licensed: (1) in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed MM who are ineligible for autologous stem cell transplant; (2) in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with MM who have received at least one prior therapy; (3) in combination with pomalidomide and dexamethasone for the treatment of patients with MM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor; and (4) as monotherapy for the treatment of patients with MM who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double-refractory to both of these drug classes [31
To date, there have been no direct comparisons between carfilzomib and daratumumab to permit an assessment of their relative impacts on HRQoL, or efficacy and tolerability endpoints. However, both carfilzomib and daratumumab have recently gone through the German Federal Joint Committee (Gemeinsamer Bundesausschuss; G-BA) early benefit assessment process according to §35a social code book V (under Arzneimittelmarkt-Neuordnungsgesetz [AMNOG; ‘Pharmaceuticals Market Reorganisation Act’]) and the respective dossiers prepared by the pharmaceutical companies are publicly available. Here, we used these public-domain dossier data to conduct a descriptive, indirect comparison of carfilzomib and daratumumab and their effects on HRQoL as reported from the ASPIRE, ENDEAVOR, CASTOR, and POLLUX trials [32
Patients with MM often experience impaired HRQoL [11
]. For example, patients enrolled in the ASPIRE and ENDEAVOR studies had EORTC QLQ-C30 global health status/QoL scores of ~ 50–60 of a maximum of 100 [24
]. It is therefore important to avoid further deterioration wherever possible. In this analysis, HRQoL deteriorations were observed across all four phase III RRMM trials included here, although indirect, descriptive comparison across these trials suggests that the risk of HRQoL deterioration is less with carfilzomib-based than with daratumumab-based therapy. Results from the phase III ASPIRE and ENDEAVOR trials also show that a carfilzomib-based regimen has benefits over comparator treatments in many QoL domains of the EORTC QLQ-C30, including both functional and symptoms subscales. The benefit was particularly apparent on the global health status scale, where significant reductions of 23% and 21% in the risk of HRQoL deterioration were observed in ASPIRE and ENDEAVOR, respectively. In comparison, in POLLUX and CASTOR, the reductions in risk of global health status/QoL deterioration were 6% with daratumumab/lenalidomide/dexamethasone versus lenalidomide/dexamethasone and 4% with daratumumab/bortezomib/dexamethasone versus bortezomib/dexamethasone, respectively. In terms of the EORTC QLQ-C30 functional subscales, HRQoL benefits were observed for daratumumab-based treatment versus comparator only on social functioning. With respect to the individual symptoms scales, significant benefits in favor of carfilzomib-based therapy over comparators were seen for the constipation subscale in both the ASPIRE and ENDEAVOR trials, and additionally for the nausea/vomiting, insomnia, appetite loss, and diarrhea subscales in the ENDEAVOR trial. In contrast, there were no significant differences on the symptom subscales between daratumumab-based therapy and comparators in the POLLUX and CASTOR trials.
To put the results of this analysis in context with other published HRQoL trials in patients with RRMM, the TOURMALINE-MM1 study of lenalidomide/dexamethasone with or without ixazomib showed no differences in EORTC QLQ-C30 scores after a median of 23 months of follow-up, and no significant difference in OS was observed between treatments [17
]. In the MM-003 study of pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone, however, combination therapy was associated with a greater probability of improved HRQoL and prolonged time to HRQoL worsening [19
]. The OS benefit in the subgroup of patients with ≥ 2 prior treatments was 5 months. In the PANORAMA-1 study, HRQoL scores after 48 weeks of treatment with bortezomib/dexamethasone, with or without panobinostat, showed no benefit, and no significant difference in OS was observed between treatments [43
Interestingly, it has been reported that there may be a relationship between improvement in HRQoL and treatment response in patients with cancer [36
]. In a sub-analysis of the ENDEAVOR trial, patients receiving carfilzomib/dexamethasone who were classified as responders (i.e., those with a partial response or better) experienced significant improvement on the EORTC QLQ-C30 global health status scale relative to non-responders [45
All four trials included in the current analysis showed improved median PFS (the primary endpoint in each trial) for carfilzomib- or daratumumab-based therapy versus comparator [23
]. Furthermore, carfilzomib was associated with a median prolongation in OS of almost 8 months, regardless of whether it was used in combination with lenalidomide/dexamethasone or dexamethasone alone [5
]. Median PFS and OS have not yet been reached for daratumumab in published reports of final analyses, so it is unclear what magnitude of efficacy benefit is associated with this agent.
Tolerability was generally similar across the four trials [23
], although there was a significantly lower incidence of peripheral neuropathy symptoms of Grade ≥ 2 with carfilzomib/dexamethasone (6%) versus bortezomib/dexamethasone (32%; p
< 0.0001) in the ENDEAVOR head-to-head trial [23
]. Indeed, bortezomib-induced peripheral neuropathy has a substantial impact on HRQoL and is difficult to manage, usually requiring reduction, interruption, or cessation of therapy [46
To the best of our knowledge, this is the first descriptive comparison of HRQoL during carfilzomib- and daratumumab-based therapy, and the first time HRQoL has been assessed prospectively in a large cohort of similar patients with RRMM (carfilzomib n
> 1700; daratumumab n
> 1000). Another strength of the trials was the very high return rates for QoL questionnaires in a population of severely ill patients, for whom completion of QoL questionnaires may be considered too demanding and/or time consuming. In addition, some patients may have died or relapsed before questionnaires could be returned. There were, however, some limitations to the study. For example, this was an indirect descriptive comparison of carfilzomib- and daratumumab-based therapy, and direct, prospective, head-to-head trials are required to explore any potential differences between these agents in their impact on HRQoL and outcome. Furthermore, as the protocol-defined treatment cycles in which HRQoL was assessed differed between trials (see Table 1
), this may have had an impact on the recorded time to deterioration. Any bias introduced in this way is expected to be minor, however, and mitigated by the use of HRs in these analyses. It is possible, however, that more frequent study visits could result in more intensive caregiver–patient interactions, with a positive impact on HRQoL. As these were prospective clinical trials, HRQoL measurements were made only during study treatment and stopped after disease progression or death. Another limitation was the potential for under-reporting of HRQoL impact as a result of different treatment durations between studies. For example, there was a maximum of eight cycles of daratumumab/bortezomib/dexamethasone in the CASTOR study, after which patients received daratumumab monotherapy. There were also other methodological differences between trials, such as different patient numbers; dates of recruitment; patient characteristics; HRQoL instruments and cut-off points used, including protocol-defined MIDs; and pre- and post-study treatments. Moreover, the open-label designs of the four studies meant that patients were aware of their treatment assignment and response, which may have affected their answers to HRQoL questions, although no analysis of potential correlations between tumor responses and HRQoL were conducted as part of the AMNOG assessment.
In conclusion, this analysis has demonstrated the feasibility of HRQoL measurement with high questionnaire return rates in large populations of severely ill patients with RRMM. Currently, carfilzomib-based therapy is the only treatment for RRMM that has demonstrated significant differences versus study comparators in OS, global health status/QoL and other functional and symptom scales. Furthermore, descriptive analysis of the available HRQoL data across trials suggests potential benefits for carfilzomib-based therapy over standard therapy, as well as over daratumumab-based therapy. With the introduction of more effective therapies, the improvements in OS over time in patients with MM mean that the disease is now a chronic disorder, and so patients’ HRQoL should be assessed regularly in prospective MM trials [47
]. There may also be a role for QoL monitoring tools and apps, such as CANKADO (https://cankado.com/
) to improve the quality of patient care.
Compliance with ethical standards
Conflict of interest
Katja Weisel has received honoraria from Amgen, BMS, Celgene, Janssen, Novartis, and Takeda; research funding from Amgen, Celgene, Janssen, and Sanofi; and has acted as a consultant for Amgen, Adaptive Biotech, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda. Heinz Ludwig has received research funding from Amgen and Takeda; speaker bureau honoraria from Amgen, Takeda, Janssen-Cilag, BMS, and Celgene; and advisory board honoraria from Abbvie, Takeda, and Amgen. Achim Rieth and Andrea Lebioda are employees of Amgen GmbH and hold shares and stock options. Hartmut Goldschmidt has received research support from Amgen, BMS, Celgene, Chugai, Janssen, Sanofi, Mundipharma, Takeda, and Novartis; speaker bureau honoraria from ArtTempi, BMS, Celgene, Chugai, Janssen, and Novartis; and is a member of advisory boards for Adaptive Biotechnology, Amgen, BMS, Celgene, Janssen, Sanofi, and Takeda.
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