Page 25 - Haematologica May 2020

Comprehensive appraisal in cancer patients
Risk parameters in multiple myeloma
That age alone is a much less well-suited discriminator for treatment designation has been shown via various risk parameters and comorbidity scores, that are usually described as patient-related factors.11,12,24-26 These involve simple measures of daily activity, such as constitution via Eastern Cooperative Oncology Group (ECOG) or Karnofsky performance status (KPS), organ function, and comorbidities. However, because the KPS/ECOG do not reflect the entire functional status of cancer patients, advances in defining patient fitness more precisely are warranted. In an analysis of 466 consecutive MM patients, the median KPS was determined to be 90%, although a precise reassessment showed this was actually 60%, i.e. 30% lower than that estimated by physicians. This clearly demonstrates that both KPS/ECOG are often over-estimated, and a more precise frailty assessment is valuable.25 In a subsequent analysis, 13 comorbid condi- tions were assessed in 801 patients. These were graded and rated according to the Common Terminology Criteria for Adverse Events (CTCAE 4.03), which includ- ed: renal-, lung- and KPS-impairment, cardiac, liver or gastrointestinal disease, disability, frailty, infection, thromboembolic events, peripheral neuropathy, pain, and secondary malignancies. In addition, age, cytogenetics via fluorescence in situ hybridization, renal function and lung disease were determined. The multivariate Cox propor- tional hazard model based on backward selection revealed five highly significant risks as relevant for OS: renal and lung function, KPS, age, and frailty (Fried defi- nition). Score weights for comorbidities were determined on the basis of regression coefficients of the prognostic factors.12 Although impairment of organ function such as lung disease had been defined as having nothing to do with MM, in line with other large MM study groups (such as both the German GMMG and DSMM study groups), patients with moderate and severe lung impair- ment and continued smoking habit were at substantial risk for treatment complications.11,12 We would, therefore, refrain from ASCT/allogeneic-SCT, triplet and quadruplet therapies in heavy smokers and/or those with impaired lung function.11,12,24-26 Moreover, disease-related factors add additional complexity in MM, such as cytogenetics, International Staging System (ISS)/revised (R)-ISS stage, bone marrow infiltration, and number of CRAB (C, hypercalcemia; R, renal impairment; A, anemia; B, bone lesions) symptoms. In addition, treatment-related factors, such as how quickly and for how long the disease responds to therapy, are critical.27-29
Frailty, organ impairment and myeloma scores
In prior organ function analyses,11,12,24-26,30 the extent of frailty in MM patients was substantial: 60% for entire (mild to severe) and 40% for severe frailty.11,12 This led to the development of the revised myeloma comorbidity score (R-MCI). This R-MCI uses weights generated via multivariate risk factor assessment with the essential risks being included therein, such as: renal and lung function, KPS, frailty and age, with the option to add cytogenet- ics.11,12 Apart from organ impairment, cytogenetic aberra- tions corroborate with impaired OS in MM patients. The analysis confirmed that cytogenetics provide independent
additional information,31-35 and that patients with unfavor- able cytogenetics had higher disease stages, adverse labo- ratory values, and reduced organ and physical function. Although cytogenetics proved to be a relevant risk factor, the analysis confirmed that others, such as physical and organ conditions, are equally important.6,7,11,12,18 Moreover, development of the R-MCI showed that the multivariate risks (renal, lung function, KPS, age, frailty) defined patients as fit, intermediate-fit, and frail, which could be improved with inclusion of cytogenetics, (but which could still be used even if this information was unavailable). Weighting of the R-MCI verified that this 9-point score defines three patient groups with clearly different survival,12 which remained true regardless of treatment or age subgroups.
Comparison of the R-MCI with others and
current questions
Comparison of the R-MCI with numerous others [CCI, Kaplan Feinstein (KF), Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI/Sorer),12 the Satariano Index24-26 or the International Myeloma Working Group (IMWG frailty score11) showed that they all divide patients into risk groups with substantially different OS. However, Brier scores determined the smallest prediction errors with the R-MCI. One reason for the comparability of the R- MCI with others was that most include risks that have some relevance in MM, namely renal and lung function, and physical condition. Compared to the initial non- weighted MCI,24-26 the R-MCI led to an improvement in group distinction, which highlights the relevance to fur- ther improve a risk score, as performed in subsequent analyses.11,12,24-26,30 Various risk scores that are used in differ- ent institutions and within clinical trials in MM patients are summarized in Table 1.18,36-38
The question is, therefore, whether one comorbidity score in MM should be put forward or whether more should be developed. Moreover, would harmonization and inclusion of biomarkers improve them?39 Another question is if MM experts will use these scores and whether treatment decisions are being improved.40,41 Whether risks determined by a score result in changes in treatment decision has not been fully addressed. Given that MM primarily affects the elderly, whose vulnerabili- ties may change over time, it is also reasonable to incor- porate serial GA throughout treatment in order to poten- tially modify therapy over time and incorporate this into tumorboards and treatment guidelines. For older, fit patients, intensive treatment with ASCT may be appro- priate, while in the very frail, with GA and high R-MCI- scores, end-of-life care discussions can be facilitated.10,42
Concrete clinical designations of the use of the R-MCI
1. We have included the R-MCI in the weekly MM tumorboard, where this is being scored before the patient is discussed at an interdisciplinary level. Web applications make it easy to obtain a score end result, as has been achieved for the R-MCI and IMWG-frailty scores.11,12,18,40 For the R-MCI, each patient’s individual risk parameters will generate an R-MCI score.
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