Frailty in multiple myeloma: the need for harmony to prevent doing harm
Authors: Sonja Zweegman, Alessandra Larocca
Journal: The Lancet Haematology (2019)

In the past decade, an expanded treatment armamentarium has led to impressive improvements in the prognosis of older patients with multiple myeloma who are ineligible for autologous stem-cell transplantation. The extent of this improvement however, is more notable in younger patients than in older patients, probably because of biological ageing. Ageing is characterised by a progressive loss of physiological reserves leading to impaired organ function, of which frailty is the phenotype.1Cardoso AL Fernandes A Aguilar-Pimentel JA et al.Towards frailty biomarkers: candidates from genes and pathways regulated in aging and age-related diseases.Ageing Res Rev. 2018; 47: 214-277Crossref PubMed Scopus (201) Google Scholar In frail patients with multiple myeloma, drugs cause more adverse events than in non-frail patients, sometimes leading to discontinuation of therapy, with a negative effect on outcome.2Bringhen S Mateos MV Zweegman S et al.Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials.Haematologica. 2013; 98: 980-987Crossref PubMed Scopus (160) Google Scholar The International Myeloma Working Group (IMWG) has developed an index to identify frail patients who might have worse overall survival and progression-free survival, increased incidence of grade III–IV non-haematological toxicity, and discontinuation rate. The score is based on age (≤75 years, 76–80 years, or >80 years), the Charlson Comorbidity Index (≤1 or >1), the Activities of Daily Living (ADL; >4 or ≤4), and instrumental ADL (IADL; >5 or ≤5), and has been validated in a separate cohort of patients.3Palumbo A Bringhen S Mateos MV et al.Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report.Blood. 2015; 125: 2068-2074Crossref PubMed Scopus (472) Google Scholar, 4Engelhardt M Dold SM Ihorst G et al.Geriatric assessment in multiple myeloma patients: validation of the International Myeloma Working Group (IMWG) score and comparison with other common comorbidity scores.Haematologica. 2016; 101: 1110-1119Crossref PubMed Scopus (127) Google Scholar Patients defined as frail with the IMWG frailty index have greater functional impairments and loss of muscle mass than non-frail patients, indicating that the index reflects biological frailty.5Stege CAM Nasserinejad K Levin M-D et al.Geriatric impairments and low muscle mass are associated with treatment discontinuation and overall survival in newly diagnosed non-transplant eligible multiple myeloma patients (nte-NDMM) treated with dose-adjusted melphalan-prednisone-bortezomib (MPV) — results of the Dutch HOVON 123 Study.Blood. 2018; 132 (1889): 1889PubMed Google Scholar However, data about ADL and IADL are absent in many studies, which precludes validation of the IMWG frailty score in clinical trials and in population-based registries. Therefore, the study by Gordon Cook and colleagues6Cook G Royle K-L Pawlyn C et al.A clinical prediction model for outcome and therapy delivery in transplant-ineligible patients with myeloma (UK Myeloma Research Alliance Risk Profile): a development and validation study.Lancet Haematol. 2019; (published online Feb 6.)http://dx.doi.org/10.1016/S2352-3026(18)30220-5PubMed Scopus (55) Google Scholar in The Lancet Haematology represents an important effort to create an easy-to-define prediction model for outcome and treatment feasibility, in the largest patient cohort analysed so far in multiple myeloma. The model consists of WHO performance status, International Staging System, age, and C-reactive protein (CRP) concentration and defines three risk groups (low, intermediate, and high), with a 35-month difference in median overall survival between the low-risk (60 months) and high-risk group (25 months). Additionally, the model predicted progression-free survival, early mortality, and treatment compliance in the datasets analysed. Importantly, the prognostic value of this model was independent of treatment and cytogenetic risk profile. Because these data are available in most studies, comparisons of the outcome of frail patients with different treatment regimens are now possible and could pave the way for frailty-adapted treatment.6Cook G Royle K-L Pawlyn C et al.A clinical prediction model for outcome and therapy delivery in transplant-ineligible patients with myeloma (UK Myeloma Research Alliance Risk Profile): a development and validation study.Lancet Haematol. 2019; (published online Feb 6.)http://dx.doi.org/10.1016/S2352-3026(18)30220-5PubMed Scopus (55) Google Scholar Yet, this score does not necessarily reflect frailty as originally defined by Fried and colleagues, based on the presence of at least three of five criteria: unintentional weight loss, self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity.7Fried LP Tangen CM Walston J et al.Frailty in older adults: evidence for a phenotype.J Gerontol A Biol Sci Med Sci. 2001; 56: M146-M156Crossref PubMed Google Scholar Although performance status indicates the average daily physical activity of patients, this assessment is made by physicians, not by patients. Accordingly, it has been reported that performance status does not reflect objective levels of physical activity. Additionally, it does not provide functional data.8Broderick JM Hussey J Kennedy MJ DM OD Patients over 65 years are assigned lower ECOG PS scores than younger patients, although objectively measured physical activity is no different.J Geriatr Oncol. 2014; 5: 49-56Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar Furthermore, CRP, which is produced by senescent cells, has been described as a variable related to the chronic inflammation associated with ageing (so-called inflammaging), albeit with low specificity.1Cardoso AL Fernandes A Aguilar-Pimentel JA et al.Towards frailty biomarkers: candidates from genes and pathways regulated in aging and age-related diseases.Ageing Res Rev. 2018; 47: 214-277Crossref PubMed Scopus (201) Google Scholar Unfortunately, the authors did not compare their score with the current gold standard, the IMWG frailty score. Therefore, it is unknown whether both scores are equal in discriminating outcomes, and whether they identify an identical frail population who would benefit less from treatment.3Palumbo A Bringhen S Mateos MV et al.Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report.Blood. 2015; 125: 2068-2074Crossref PubMed Scopus (472) Google Scholar That brings us to the main issue of defining older patients who will not benefit from treatment and who might even experience early mortality because of treatment. Although frailty is generally perceived as the underlying cause, there is currently no uniform definition of frailty in clinical practice. Additionally, the discriminative power of current scores is still insufficient to select patients who are suitable for therapy or in whom benefit will be negligible, leading to the decision not to start treatment. Therefore, further improvement of a frailty score is of importance. Notably, the value of a frailty score might be dependent on treatment, as novel treatments, including immune therapy, could overcome the negative effect of frailty on the clinical outcome. Indeed, a recent trial investigating bortezomib plus melphalan plus prednisone with or without the monoclonal antibody daratumumab found no difference in outcome between patients aged 75 years and older and those younger than 75 years. However, the IMWG frailty score was not used in that study and drawing conclusions is therefore difficult.9Mateos MV Dimopoulos MA Cavo M et al.Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma.N Engl J Med. 2018; 378: 518-528Crossref PubMed Scopus (595) Google Scholar Preliminary data from IMWG-defined frail patients do support the feasibility of ixazomib and daratumumab in unfit and frail patients.10Stege CAM Nasserinejad K Levin M-D et al.Efficacy and tolerability of ixazomib, daratumumab and low dose dexamethasone (IDd) in unfit and frail newly diagnosed multiple myeloma (NDMM) patients; first interim safety analysis of the phase II HOVON 143 Study.Blood. 2018; 132 (abstr).: 596Google Scholar Cook and colleagues have provided an easy-to-use prognostic risk model. In the same way as others, they not only implemented patient characteristics but also disease characteristics, which are known to increase discriminative power. In order to guide physicians in the treatment of older patients with multiple myeloma, the different frailty scores should be further improved and harmonised. This will allow comparisons of outcomes of frail patients and development of novel, effective, and feasible treatment regimens. As frailty is a consequence of biological ageing, it would be useful to explore the added value of biomarkers for ageing.1Cardoso AL Fernandes A Aguilar-Pimentel JA et al.Towards frailty biomarkers: candidates from genes and pathways regulated in aging and age-related diseases.Ageing Res Rev. 2018; 47: 214-277Crossref PubMed Scopus (201) Google Scholar SZ reports grants from Janssen and Takeda on research areas related to the submitted work, and from Celgene, on research areas outside of the submitted work. AL reports personal fees from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda. A clinical prediction model for outcome and therapy delivery in transplant-ineligible patients with myeloma (UK Myeloma Research Alliance Risk Profile): a development and validation studyWe have developed and externally validated a risk profile for overall survival containing widely available clinical parameters. This risk profile could aid decision making in patients with multiple myeloma ineligible for stem-cell transplantation, but further external validation is required. Full-Text PDF Open Access