Assessment and treatment of frail patients living with multiple myeloma. A guideline on behalf of the <scp>UK</scp> Myeloma Research Alliance Frailty Group

There have been considerable therapeutic advances within the last decade in the field of multiple myeloma (MM) which have translated into superior outcomes for the majority of patients living with this condition. Concurrently, there has been increasing focus on frailty in MM, appreciating the importance of balancing overall survival with healthy life years through minimising treatment-related toxicities and maintaining quality of life. This guideline explores how to best identify and assess frailer patients living with MM. We outline the current therapeutic landscape in this patient population in addition to exploring emerging areas of interest in the field of frailty. This guideline was developed and approved by the UKMRA frailty subgroup, with the methodology aligning with the BSH process. The Development and Evaluation (GRADE) nomenclature was used to evaluate the levels of evidence and to assess the strength of recommendations (see www.gradeworkinggroup.org). Improving healthspan (healthy ageing) as well as prolonging lifespan are hugely important issues for both medicine and society in general. The difference between lifespan and healthspan encompasses the influence of not only disease but also more rapid physiological deterioration consequent to concomitant illness and polypharmacy, further augmenting physiological decompensation—frailty. Frailty refers to acquired age-related vulnerability resulting from this decline in physiological systems which compromises a person's ability to cope with everyday or acute stressors.1, 2 Frailty is associated with an increased risk of adverse clinical outcomes, with cancer patients experiencing poorer tolerance of anti-cancer chemotherapy and higher discontinuation, toxicity and overall mortality.3 Multiple myeloma (MM) is the second most common haematological malignancy and is characterised by uncontrolled proliferation of malignant plasma cells within the bone marrow. It accounts for 1%–2% of all malignancies with an average age of diagnosis of 69 years.4 Clinical manifestations of MM include immunocompromise, lytic bone lesions with an increased risk of fracture, renal impairment and hypercalcaemia. Treatment often comprises combinations of conventional and novel systemic anti-myeloma agents or, increasingly, targeted immunotherapy. Autologous stem cell transplants are recommended in younger, fitter patients. Treatment often results in adverse effects including, but not limited to: infection, peripheral neuropathy, thromboembolism, diarrhoea, skin rashes and, with the advent of targeted treatment such as T-cell engagers and chimeric antigen receptor T-cell therapy (CAR-T), cytokine release syndrome and neurocognitive toxicity.5 The prevalence of frailty, by heterogeneous definitions, has been reported at 25.1%–54%6, 7 in newly diagnosed MM patients. At disease progression, it is recognised that patients frequently experience an evolution of their frailty status, with the prevalence of frailty at relapse having been reported to be as high as 73.6%.8 This is not solely due to health-related vulnerabilities inherent with advancing age but also complications associated with the re-emergence of MM as well as treatment-emergent toxicity from therapy already delivered.9-11 Studies exploring the longitudinal nature of frailty in MM are awaited.12-14 Evidence suggests that the coexistence of frailty may result in poorer tolerance of treatment, decreased efficacy of treatments and overall compromised clinical outcomes.15, 16 When considering frailty as a distinct biological syndrome, it is often defined according to a ‘frailty phenotype’17 (grip strength, walking speed, physical capacity, level of energy and weight loss) or a ‘cumulative deficit model’18, 19 (deficits in physical or cognitive ability, functional impairment, abnormal laboratory values and comorbidities). However, there is no easy or accepted means of assessing the frailty phenotype while the deficit model is overly burdensome.20 More simple screening tools include the Rockwood Clinical Frailty Score (CFS) which assesses frailty according to day-to-day functioning and can be undertaken in a matter of minutes,19 the Vulnerable Elders Survey-13 (VES-13)21 which is a 13-item function-based questionnaire validated in oncology settings22 and the Geriatric-823 (G-8) questionnaire which includes nutritional assessment. The American Society of Clinical Oncology (ASCO) recommends the VES-13 or the G-8 questionnaire for older patients receiving chemotherapy24 although such screening tools are yet to be embedded in routine MM clinical practice. A number of frailty tools specifically for MM patients have been validated, either in clinical trial populations, the real world or both, that assign patients to either a group or a score which determines their frailty status. The International Myeloma Working Group Frailty Score (IMWG-FS) is a myeloma-adapted geriatric assessment (GA) clinical scoring system that includes not only functional but also clinical assessments and is regarded as the ‘gold standard’.15 This score identifies the fit, intermediate-fit and frail among older (≥65 years) MM patients. Retrospective application of this score has shown that the intermediate-fit and frail are more likely to stop therapy prematurely, suffer more toxicity and have shorter remissions and shorter overall survival, with the frail group having the worst outcomes.25 However, this complex score is difficult to apply in busy clinics and has not been rigorously tested prospectively. Other tools have been developed which aim to improve on the IMWG-FS in delineating patients that may be vulnerable and subsequently have inferior outcomes based on increased discontinuation rates or toxicities driven by their frailty status (Table 1). Fit Intermediate fit Frail Non-frail Frail Clinical trial Real world Fit Intermediate fit Frail Clinical trial Real world Low risk Medium risk High risk Clinical trial Real world I II III IV All these scoring systems include an assessment of functional status, utilising different tools which can include IADL (instrumental activities of daily living), ADL (activities of daily living), PS (performance status), KPS (Karnofsky performance scale) and ECOG (Eastern cooperative oncology group performance status). However, the UK Myeloma Research Alliance Myeloma Risk Profile (UK-MRP) and Mayo frailty clinic score also include frailty biomarkers (CRP/ISS and NT-proBNP respectively)28, 29 while the revised myeloma co-morbidity index (R-MCI) has the option of including MM-related risk factors (cytogenetics).27 The geriatric assessment-based International Myeloma Working Group frailty score (IMWG-FS) was derived from pooled analysis of 869 newly diagnosed myeloma patients enrolled into three prospective clinical trials, with a median age of 74 years.15 The IMWG-FS is most frequently employed to assess frailty in randomised controlled trials (RCTs) and non-RCTs.30 Although the IMWG-FS is still considered to be the ‘gold standard’ in the newly diagnosed population,11 an often-cited challenge in embedding this scoring system into day-to-day clinical practice is the need to complete 31 categories of information, which can be self-reported by the patient, but nonetheless takes between 5 and 7 min on average. Therefore, the appeal of a simpler scoring system is appreciable, and the modified IMWG frailty score may represent a pragmatic approach to this issue. The modified IMWG frailty score also benefits from enabling frailty assessments as post-hoc analyses of clinical trials.31-34 However, this score may be more weighted towards to the chronological age, rather than reporting the diversity of fitness phenotypes that exist out with ageing and may oversimplify the diversity of frailty phenotypes given the binary classification as either frail or non-frail. In addition, the modified frailty score may be vulnerable to subjective bias in that the physician reports the ECOG performance status which is used as a surrogate for physical function (IADL/ADL).35 Indeed, a recent prospective study comparing the IMWG-FS with the modified IMWG frailty score in 300 older MM patients found that the modified frailty score over- and underestimated the frailty status in an equal proportion of patients at approximately 10% per group.36 This discordance is compounded when using the patient-reported PS in the modified frailty tool due to loss of the granular detail embedded within the ADL and IADL assessments.36 The Revised Myeloma Co-Morbidity Index (R-MCI) was developed following a single-centre analysis of 801 newly diagnosed MM patients between 1997 and 2012. The analysis included transplant eligible patients with a median age of 62 years.27 A limitation of the R-MCI is the inclusion of lung function assessment, which, while performed more routinely in the transplant eligible population, is less frequently employed in the day-to-day care of transplant ineligible patients. Cytogenetic data can also be included on the premise that this is an independent prognosticator in MM, thereby incorporating variables relating to disease biology rather than frailty alone, and, as such, the tool is also valid where cytogenetic data are unavailable. A prospective review of 347 consecutive patients treated at a single centre, comparing the risk group stratification of the R-MCI with the IMWG-FS, showed concordance between low-risk groups with the IMWG-FS criteria (26% R-MCI vs. 30% IMWG-FS) but divergence with the intermediate- and high-risk groups (R-MCI vs. IMWG-FS: 60% vs. 14% intermediate risk, 14% vs. 34% high risk respectively).37 Similarly, an analysis of a smaller cohort of 40 older patients with newly diagnosed MM found limited concordance between the IMWG-FS scoring system and the R-MCI, with the R-MCI more frequently classifying patients as intermediate fit in preference to frail (IMWG-FS 37.5% intermediate fit, 55% frail vs. R-MCI 72.5% intermediate fit, 17.5% frail).38 The UK-MRP was developed following the analysis of outcomes of 2372 non-transplant patients enrolled in two medical research council (MRC) randomised controlled trials (Myeloma IX and Myeloma XI) and defined three distinct groups by outcomes classified as low risk, medium risk and high risk.28 It represents more of a vulnerability score rather than a true frailty index and it is notable that this tool also depends upon physician assessment of performance status and so may too be vulnerable to bias. However, it has been validated in a large retrospective analysis utilising the Danish national MM registry which concluded that the UK-MRP score is a robust risk assessment tool for older MM patients with a median survival of 55 months in the low-risk group versus 35.9 and 13.9 months in the medium- and high-risk groups respectively.39 Concordance of the UK-MRP scoring system against the IMWG-FS has been reported to occur in 47.5% of patients enrolled in the Myeloma XIV FiTNEss trial: MRP low risk aligns with IMWG-FS fit in 46.2%, MRP high risk aligning with IMWG-FS frail in 58.2%. However, 13.2% of patients were deemed to be high risk by MRP who were assessed as fit by IMWG-FS.40 This will be prospectively assessed, including the dynamic in the UKMRA Myeloma FiTNEss study The Mayo clinic frailty score was developed prospectively following review of patients between and at a single and included both and patients with of patients having a performance status of 2 or A review in comparing the of the IMWG-FS, R-MCI and Mayo clinic frailty score concluded that the IMWG-FS and R-MCI were the most tools for risk and a cohort study comparing risk groups found the Mayo risk score was more likely to a patient as intermediate risk versus high risk when to the IMWG-FS vs. IMWG-FS: 55% intermediate risk vs. high risk vs. It is notable that only a of have the application of frailty scoring in the younger, and the most robust evidence for utilising these tools in clinical practice is in deemed to be transplant ineligible or older When clinical trial outcomes for less fit MM it is notable that most frailty outcomes following analyses of enrolled patients which with that to evaluate the of frailty on treatment Therefore, there is an of clinical the outcomes of but there are more limited data how such treatments can be modified to outcomes in of frailty. In addition, when considering treatment also be given to for a prospective cohort study reported that the majority of MM patients years cognitive and functional as a while study showed that of MM patients a shorter survival in of quality of It is recognised that frailty in MM patients is a dynamic which can both improve and decline in to Indeed, a study reported that of newly diagnosed MM patients showed an in their frailty status at following treatment the and The assessed frailty in patients with a median age of years and showed that of newly diagnosed myeloma patients no in their IMWG-FS at months following treatment while and in equal In addition, as the of the treatment landscape to and given that a proportion of patients who to therapy may not on to further treatments at disease it is that treatment outcomes are from the of Therefore, frail and intermediate-fit patients in in addition to factors that to the frailty status, is to toxicity where improve outcomes and quality of life. 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However, all patients in the study were years and of patients were frail by modified frailty A analysis of outcomes according to frailty that frail patients or ECOG PS rather than to from the with a of with no The median age in the trial was years and 10% a PS the of was in both with the in the study reported as in the group to for the the of patients years limited the to which this be recommended for older patients. The 2 study the and efficacy of in newly diagnosed patients with a median age of of were modified IMWG frailty of patients were classified as intermediate fit or frail with treatment due to an adverse The rates were to the study and was the study the efficacy of versus in patients who were either ineligible for stem cell transplant or for a All patients were PS and a frailty score a median age of and deemed transplant ineligible in both the at months was in the versus in the with higher rates of treatment discontinuation in the The UKMRA Myeloma XIV FiTNEss study a approach to treatment in and frail MM patients. 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