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 capability, in the UKMRA Myeloma FiTNEss study (NCT03720041). The Mayo clinic frailty score was developed prospectively following review of 351 patients between 2007 and 2011 at a single centre and included both transplant-eligible and transplant-ineligible patients with 19% of patients having a performance status of 2 or more.29 A review in 2019 comparing the utility of the IMWG-FS, R-MCI and Mayo clinic frailty score concluded that the IMWG-FS and R-MCI were the most comprehensive tools for risk stratification30 and a cohort study comparing risk groups found the Mayo risk score was more likely to define a patient as intermediate risk versus high risk when compared to the IMWG-FS (Mayo vs. IMWG-FS: 55% intermediate risk vs. 36%, 8% high risk vs. 34%).37 It is notable that only a minority of studies have explored the application of frailty scoring in the younger, transplant-eligible population,27, 29, 41 and therefore, the most robust evidence for utilising these tools in clinical practice is in those deemed to be transplant ineligible or older (>65 years). When appraising clinical trial outcomes for older, less fit MM patients, it is notable that most studies report frailty outcomes following post hoc analyses of enrolled patients which contrast with studies that seek to primarily evaluate the impact of frailty on treatment outcomes. Therefore, there is an abundance of clinical studies detailing the beneficial outcomes of newer regimens, but there are more limited data addressing how such treatments can be modified to optimise outcomes in light of frailty. In addition, when considering treatment options, consideration should also be given to health outcome preferences for each individual patient; a prospective cohort study reported that the majority (75%) of MM patients aged >70 years rated cognitive and functional well-being as a priority above survival42 while another study showed that 42% of MM patients would accept a shorter progression-free survival (PFS) in favour of improved quality of life.43 It is recognised that frailty in MM patients is a dynamic process which can both improve and decline in response to therapy. Indeed, a population-based study reported that 15% of newly diagnosed transplant-ineligible MM patients showed an improvement in their frailty status at 1 year following treatment initiation, 26% remained the same and 33% deteriorated.44 The M-FRAIL study45 assessed frailty in 99 real-world patients with a median age of 72 years and showed that 68.7% of newly diagnosed myeloma patients had no change in their IMWG-FS at 12 months following treatment initiation while 7.1% improved and deteriorated in equal measure.46 In addition, as the complexity of the treatment landscape continues to evolve and given that a significant proportion of patients who respond to initial therapy may not go on to receive further treatments at disease progression,47, 48 it is imperative that treatment outcomes are optimised from the point of diagnosis. Therefore, identifying frail and intermediate-fit patients in clinic, in addition to addressing factors that contribute to the frailty status, is vital to minimise toxicity where possible, improve outcomes and maximise quality of life. This is in keeping with a position statement from the MM scientific advisory group of Australia, which recommends that frailty assessment is undertaken for all older adults at diagnosis, advocating commencing treatment at lower doses in the frail/intermediate-fit patients.49 Similarly, the European Myeloma Network (EMN) have acknowledged the need to balance efficacy with toxicity, which may be of greatest importance in the frail/intermediate-fit patients.15, 50 The standards of care for treating newly diagnosed non-transplant eligible patients have evolved considerably over the last decade with upfront regimens now commonly including three or four drug regimens. Such regimens include daratumumab, lenalidomide, dexamethasone (DRd);51 daratumumab, bortezomib, melphalan, prednisolone (D-VMP);32 bortezomib, lenalidomide, dexamethasone lite (VRdlite);52 isatuximab, bortezomib, lenalidomide, dexamethasone (IsaVRd)53-55 and daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd).56 The SWOG S0777 trial demonstrated the superiority of VRd to Rd in newly diagnosed MM patients not intending to undergo an immediate autologous stem cell transplant.57 A subsequent phase 2 study in the transplant-ineligible population explored the efficacy of the modified VRd regimen (VRD lite) in patients who had a median age of 73 years.52 While only 14% of the patients had a performance status of 2 or more, it is notable that VRDlite (weekly bortezomib, lenalidomide 15 mg, dexamethasone 20 mg) achieved a PFS of 41.9 months that was superior to the original VRd regimen.52 This hints that dose modification of this regimen may not compromise clinical outcomes. The MAIA study reported the superiority of adding an anti-CD38 antibody to an IMID backbone (Rd-lenalidomide, dexamethasone) resulting in a PFS of 61.9 months compared to 34.4 months with Rd. alone.51 A post hoc frailty subgroup analysis using the modified IMWG frailty score revealed that while non-frail patients have a longer PFS than frail patients, the benefit of the triplet regimen compared to the doublet was observed across all frailty subgroups.31 However, frail patients had a higher incidence of serious treatment emergent adverse events and non-haematological adverse events in both DRd and Rd. arms.31 Frail patients treated with DRd reported a sustained improvement in quality of life and physical functioning with a longer time on treatment when compared to frail patients treated with Rd.58 Similarly, the ALCYONE study comparing D-VMP to VMP in the transplant-ineligible population showed a higher response rate and overall survival benefit with the four-drug regimen, with this benefit also being observed across all frailty subgroups.32 The IMROZ53 and the BENEFIT54 studies have evidenced the superiority of IsaVRD compared to VRD or IsaRD, respectively, in newly diagnosed non-transplant-eligible patients. However, all patients in the IMROZ study were 1.54 While the superiority of IsaVRD was confirmed in both studies, with the 60-month PFS in the IMROZ study reported as 63% in the IsaVRD group compared to 45.2% for the control group,53 the paucity of patients over 80 years old limited the extent to which this regimen could be recommended for older patients. The phase 2 single-arm REST55 study explored the tolerability and efficacy of IsaVRD in 51 newly diagnosed transplant-ineligible patients with a median age of 77 years, of whom 31% were ≥80 years. By modified IMWG frailty score, 86% of patients were classified as intermediate fit (41%) or frail (45%), with 8% discontinuing treatment due to an adverse event. The MRD negativity rates were similar to the BENEFIT53 study and 18-month PFS was 78%.55 Finally, the CEPHEUS56 study explored the efficacy of D-VRd versus VRd in patients who were either ineligible for autologous stem cell transplant (ASCT) or opted for a deferred transplant. All patients were PS 0–2 and had a frailty score ≤1. With a median age of 70 years, and 73% being deemed transplant ineligible in both arms, the PFS at 54 months was 68.1% in the D-VRd arm versus 49.5% in the VRd arm with higher rates of treatment discontinuation in the VRd cohort.56 The UKMRA Myeloma XIV FiTNEss study explored a risk-adapted approach to managing treatment in unfit and frail MM patients. Treatment doses (ixazomib, lenalidomide, dexamethasone) were modified according to frailty status in the interventional arm versus physician-led dosing in the standard of care arm. There was an improved overall survival in the intention-to-treat population with the risk-adapted approach, with a median follow-up of 14.7 months, with overall response rates being maintained across both groups.60 The greatest benefit in terms of minimising early treatment cessation was observed with the risk-adapted approach in the unfit patients according to the IMWG-FS.60 Lastly, steroids continue to form the backbone of almost all MM regimens. However, it is well recognised that steroids have significant side effects which include, but are not limited to, sleep deprivation,61 cataracts,62 high blood sugars63 and muscle atrophy64 and tend to be poorly tolerated in older patients.65 Therefore, the phase III study of continuous Rd. versus nine cycles of Rd. followed by R alone in intermediate-fit MM patients is reassuring in demonstrating that discontinuing steroids after nine cycles of Rd. did not jeopardise outcomes.65 The IFM2017-03 phase III study explored a steroid-sparing regimen in newly diagnosed frail (≥2 IMWG-FS) MM patients comparing daratumumab and lenalidomide (DR) to Rd. and reported improved PFS (DR 53 months vs. Rd. 22.5 months) and OS (DR not reached vs. Rd. 47 months) with a similar safety profile being observed in both arms.66 Therefore, consideration should be given to discontinuing steroids when an adequate remission has been achieved. The complications of relapsed MM can accelerate a decline in frailty status, and therefore, consideration should be given to treating patients at biochemical progression to minimise this risk.67 There are little data exploring the direct impact frailty may have on the treatment of relapsed and refractory MM. However, many studies have included older, transplant-ineligible patients and, in common with younger cohorts, triplet regimens are preferred to doublets and tend to be well tolerated with superior outcomes and on occasions lower discontinuation rates.68-72 In addition, it remains good practice to consider class switch at disease progression and to consider additional treatments, such as a monoclonal antibody, where a patient is naïve to these agents. Many new therapies have shown remarkable efficacy in the relapsed setting (bispecific antibodies, antibody drug conjugates, CAR-T-cell therapy) and it is likely that, with accruing evidence, they will be employed earlier in the treatment pathway.73-78 As such, it is important to appreciate that their considerable efficacy does not necessarily correlate with toxicity. Indeed, the differing toxicity profiles reflect differing mechanisms of action, and emerging clinical experience suggests that T-cell engaging therapies can be given safely to many frailer patients, with the application of dose modifications. In light of this, it is important to consider which side effects could contribute to a patient's frailty phenotype and how to mitigate these toxicities to enable all patients, where possible, to have access to the most effective treatment. It is notable, however, that the landmark studies for the newer classes of drugs favoured the recruitment of patients with a younger age and good performance status, as summarised in Table 3. Belantamab mafodotin, an antibody drug conjugate, in combination with bortezomib and dexamethasone, has shown superior efficacy to daratumumab, bortezomib and dexamethasone (DVD) in the DREAMM 7 phase III randomised controlled trial (PFS 36.6 vs. 13.4 months).73 However, almost all patients (96%) had a performance status ≤1 (Table 3). Belantamab is known to result in off-target damage to corneal cells as evidenced by 79% of patients in the experimental arm reporting an ocular event, with 22% reporting grade ≥3 blurring of vision.73 Similarly, the DREAMM 8 study evidencing the superiority of belantamab, pomalidomide and dexamethasone (BPd) compared to pomalidomide, bortezomib and dexamethasone (PVd) had a similar incidence of grade ≥3 blurring of vision (17%).74 However, it was noted that the ocular events had a high rate of resolution (between 92% and 100%)74 and that this toxicity did not impact on patient assessed quality of life in either study. Nonetheless, the impact of such side effects in an older, less fit population remains unexplored potentially adding another dimension to the frailty phenotype particularly in reference to ADLs and IADLs. Bispecific antibodies show considerable efficacy in the relapsed/refractory population, with overall response rates varying from 61% to 63% in heavily pretreated MM.75-77 Particular toxicities relate to the recruitment of T cells, with grade 1–2 cytokine release syndrome being reported in up to 77% of patients.75 Importantly, a significant side effect of this class of drugs is infection, which is frequently observed, particularly with the B-cell maturation antigen (BCMA) targeting bispecific antibodies, elranatamab and teclistamab.76, 77 In the MagnetisMM-3 and MajesTEC 1 studies, all grade infections occurred in 69.9% and 76.4%, respectively, with 39.8% and 44.8%, respectively, experiencing grade 3–4 events. Importantly, 6.5% of patients in the MagnetisMM-3 trial and 7.8% of patients in MajesTEC-1 suffered fatal infections.74, 75 Both studies were conducted during the COVID-19 pandemic, and patients were not consistently offered immunoglobulin replacement therapy, which has since been proven to lower the risk of infection.81, 82 A retrospective analysis of real-world outcomes with teclistamab in older adults (age ≥70 years) included 72.8% frail and 46.9% ultra-frail patients (according to the modified frailty score), which showed a comparable PFS and overall survival (OS) in frail versus non-frail patients but a higher incidence of grade ≥2 CRS and ≥2 ICANS in frail patients.83 Similarly, there was a significant increase in infections in the frail patients (fit vs. frail: all grade 45.5% vs. 74.6% respectively; grade 3+ 9.1% vs. 28.8% respectively).83 Therefore, attention must be paid to how such treatments may be safely offered to older, frailer patients. One approach, alongside immunoglobulin replacement, may be to increase the interval between doses when a response has been achieved, which has been proven to attenuate the infection risk.84 Talquetamab, a G-protein-coupled receptor, family C, group 5, member D (GPRC5D) targeting bispecific antibody, shows response rates of between 64% and 70% in relapsed/refractory MM with grade 3–4 infections occurring in 7%.75 Alternative off-tumour, on-target toxicities are notable and include all grade skin changes (67%–70%), dysgeusia (57%–63%), nail changes (27%–57%) and weight loss (30%–32%).75 Therefore, slimmer, frailer or malnourished patients may be less able to withstand such toxicities; we await results from studies that are exploring interventions to minimise such toxicities (TALISMAN EU trial no 2023–506260-14) and how best to utilise this treatment in older, frailer patients (UKMRA iFIT study). CAR-T-cell therapy is not yet routinely available in either newly diagnosed or relapsed/refractory patients in many countries, but this treatment remains a highly promising option throughout the treatment pathway. The phase 1b/2 CARTITUDE 1 study reported an overall response rate of 97% in 97 patients who had received a median of six prior therapies.78 The results of the CARTITUDE 4 study,79 exploring the efficacy of cilta-cel in the relapsed/refractory population with a median age of 61.5 years and performance status of ≤1, may offer a promising option for older patients in this setting with overall survival at 30 months being 76.4% in the cilta-cel arm versus 33.6 months in the standard of care arm.79 The KarMMa-3 study explored ide-cel in relapsed/refractory patients with a median age of 63 years and a median of three prior lines of treatment, reporting a median PFS of 13.3 months versus 4.4 months with standard of care regimens.80 The results of CARTITUDE 5 (NCT04923893) are eagerly awaited to determine the efficacy of upfront cilta-cel for transplant-ineligible patients with a frailty score of 0–1 although a notable omission from the control arm (RVd) is an anti-CD38 antibody. A recent meta-analysis of 558 patients from 14 studies exploring the safety and toxicity of anti-BMCA CAR-T-cell therapy in older adults concluded that overall response rates are similar in patients >65 years when compared to younger patients, with similar rates of CRS being observed but a higher incidence of ICANS at 15% versus 6% in younger patients.85 Similarly, a real-world study of 136 patients receiving CAR-T-cell therapy, of whom 61% were classified as frail according to the modified IMWG score, showed similar rates of CRS but higher rates of all grade ICANS in the frail versus the non-frail group with an inferior overall survival also being seen in the frail population.86 Supportive care interventions in frail MM patients may be of particular importance in that maintaining a haemoglobin >80 g/dL may mitigate anaemia-induced fatigue and zolendronic acid continues to be recommended for reducing the incidence of skeletal-related events. Prophylactic levofloxacin reduces febrile episodes and mortality if given during the first 12 weeks of induction therapy in newly diagnosed MM. Vaccinations (influenza, varicella zoster, pneumococcal) are of increasing importance with the advent of targeted immunotherapies, enhancing protection against seasonal infections with additional acyclovir as herpes zoster prophylaxis. Lastly, immunoglobulin replacement is recommended for patients receiving immune effector therapies (bispecific antibodies and CAR-T-cell therapy) to reduce the infection risk.87 The preferred tool for assessing frailty in all older adults is the Comprehensive Geriatric Assessment (CGA) which has been shown to improve survival and functioning in secondary care settings.88 Both the International Society for Geriatric Oncology (SIOG)89 and ASCO46 guidelines recommend that frailty domains requiring review in older cancer patients include function, co-morbidities, falls, nutrition, cognition and mood/mental health. SIOG also recommends assessment of polypharmacy and social support and activities, while ASCO recommends toxicity risk prevention tools, mortality prediction tools and estimates of non-cancer-based life expectancy ≥4 years.24, 89 Such assessments are arguably more holistic than the IWMG frailty score and incorporate additional MDT members which may be an area of consideration in the future. Re-configuration of MDTs could enable frailty to be placed centre stage in care and decision-making, and it is notable that the UK national guidelines for frailty management in oncology services set out an ambition for frailty pathways and/or specialist onco-geriatric services to be developed and delivered alongside expert geriatricians and patients.90 These guidelines advocate an MDT approach to frailty with representation from physicians, nurses, physiotherapists, occupational therapists, dieticians, pharmacists, social workers and the general practitioner.90 While there can be little doubt that such a service could be transformative, resources may continue to restrain such ambitions, although shared learning upon integrating even some of these suggestions will undoubtedly be invaluable. Additionally, there is the ongoing need to further evidence the benefit of individual interventions, such as exercise programmes, which appear to be feasible but there are little robust data supporting the impact on disease or treatment-related symptoms.91 PROMS (patient-related outcome measures) are questionnaires that empower patients to directly share their experiences of quality of life, side effects and function and will therefore be important in tracking the evolution of frailty from a patient perspective. PROMS have also been shown to detect disease progression prior to clinical progression in MM, hinting that this could correlate with a change in symptoms and potentially frailty, in addition to prognosticating for PFS and OS.92 Similarly, there is emerging evidence that measuring activity levels with wearable devices may enable early detection of health-related issues, facilitating earlier intervention, as well as an adjunct to exercise training.93 Consideration of patient-related factors which may impact upon treatment adherence and tolerance may aid in the management of frail patients. Studies suggest that MM patients and their carers suffer considerable psychological distress which includes anxiety, depression and post-traumatic stress disorder (PTSD) in between 22.6% and 25% of patients and 15.3%–44.4% of caregivers.94 Dependence on carers, carer fatigue, financial barriers and cognitive impairment can have a considerable impact on treatment success above and beyond individual drug toxicities. Recognition of such factors is predicated on good working relationships between healthcare providers and patients with clinical nurse specialists, or their equivalents, often proving to be invaluable. However, it is difficult to objectively quantify the meaningful impact of such team members and therefore exploration of these realtionships and how best to optmise them may also be of critical importance. As the treatment landscape in myeloma continues to evolve at pace, embedding real-world evidence becomes important in terms of understanding outcomes for patients who may otherwise be deemed too frail to enter clinical studies. However, to interpret such evidence, assessing frailty must be considered essential to enable real-world outcomes to be interpreted from a frailty perspective. The advent of frailty-adapted studies, with permissive inclusion criteria, such as the Myeloma XIV FitNEss study95, 96 and its successor study UKMRA Myeloma XVIII iFIT, will become critically important in understanding how to integrate therapeutic advances in this more challenging patient group, including novel immunotherapies. Attention toward identifying and optimising the most vulnerable myeloma patients, the ultra-frail group, must also be considered. This patient cohort can be identified according to IMWG-FS as frail (score ≥3) and scoring as high risk by MRP and represents the most challenging group to optimise.11 It is arguable that the dominant issue impacting on outcomes in this subgroup of patients is indeed frailty rather than the myeloma itself.9 The recent Myeloma XIV FiTNEss study confirmed this assertion in demonstrating that early treatment cessation was reduced significantly with the incorporation of an adaptive treatment approach in IMWG-FS unfit patients, with little effect observed in IMWG-FS frail patients.97 We await the results of the ULTRA FRAIL-MM trial, which is exploring a go-slow approach to treatment in newly diagnosed ultra-frail patients and may inform how best to optimise outcomes.98 Biomarkers continue to hold considerable appeal, both in terms of prognostication and predictive function, but, as a recent EMN position paper acknowledged, biomarkers for frailty in MM are yet to be extensively studied and further work is needed in the context of clinical trials to begin to explore their potential.14 Finally, emerging areas of interest in the field of frailty include senolytics,99 sarcopenia,100 the gut microbiome101 and the metabolome.102 While detailed exploration of such evolving fields of interest is beyond the scope of this paper, senolytics (therapeutics that seek to delay age-related disease, promote healthspan and prevent frailty) show considerable promise in preclinical studies, with emerging clinical studies awaited.103 Senolytic agents such as nicotinamide riboside hint at the possibility of conferring resilience against age-related conditions,104 while metformin has been proven to improve age-related decline in mice, including improved exercise tolerance, locomotor activity and reduced cataract development.104 Human observational studies suggest that metformin reduces frailty105 and all-cause mortality.106 Other therapeutics within this field being explored include dasatinib, fisetin and quercetin.103 Sarcopenia, which is characterised by loss of muscle mass and decreased muscle strength or physical function, predicts toxicity and treatment response in haematology patients and is a predictor of OS and non-relapse mortality.100 Importantly, sarcopenia is reversible with physical exercise and nutrition interventions.100 The gut microbiome is known to exert an effect on inflammation, which in turn may impact on frailty in addition to the recognised shift to a pro-inflammatory phenotype with advancing age.101 A study of 1551 older adults found the frailty phenotype to be associated with a reduction in microbiome diversity107 while a randomised controlled trial of 612 adults evidenced that adhering to a Mediterranean diet was associated with enrichment of the gut microbiota and reduced frailty.108 Finally, a systematic review in the field of metabolomics found that certain amino acids were lower in frail subjects while glutamate and glutamine were higher.102 In addition, metabolite derivatives, such as carnitine, were shown to be reduced in frail patients advancing our understanding of how frailty and metabolites may be associated.102 Frailty in MM remains a complex and evolving field. Validated tools are essential to enable identification of frail MM patients in the clinical setting to assist in optimising outcomes resulting in tailored treatment selections and dose modifications. Future developments may incorporate a holistic, evidence-based approach to assessing and managing frail patients, while deeper understanding of modifiable risk factors continues to evolve. All authors contributed to the writing and reviewing of the manuscript. Not applicable.
Moore et al. (Wed,) studied this question.
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