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M. Engelhardt et al.
   Training and validation analyses of the R-MCI showed well-discriminated risk profiles in terms of both PFS and OS for fit, intermediate fit, and frail patients.12 This was true both for more intensively and less intensively treat- ed MM patients.12 Moreover, if MM patients were risk- assessed via the R-MCI rather than the IMWG-frailty score, Kaplan-Meier analysis produced more clearly sepa- rated PFS and OS curves with the the R-MCI than with the IMWG-frailty score.11
Importantly, if patients are intermediate-fit or frail by R-MCI, precautions for dose reduction of systemic treat- ment can be made: i.e. if advanced frailty in MM patients is observed, dose reductions can be discussed, including whether the disease aggressiveness needs effective anti- MM treatment to be performed in spite of the patient's frailty. Today, it seems important, given the widely differ- ent anti-MM treatment options, that the frailty scoring specifically warns MM experts that complications with intensive treatment may occur. As many precautions as possible can then be taken while treatment is being given, such as inpatient rather than outpatient treatment, obser- vation on the ward until complications no longer occur, prophylactic medications, etc. In line with this, in their joint EMN-paper,7 the European Myeloma Network (EMN) consensus has stated that in fit MM patients, effi- cient antimyeloma therapy with the aim of deep remis- sion is key, whereas in unfit or frail patients, the priority is to maintain a good balance between therapy efficacy and safety.
2. Useful dose adaptations have been recommended for individual antimyeloma agents and are published as such in guidelines and chemotherapy manuals.6,7,43
3. The R-MCI has also been included in study protocols before therapy initiation and at the end of treatment. This can assess whether a patient's constitution did improve over time, and whether this was associated with myelo-
ma response and better functional comorbidity tests (Table 1).21,44
4. The R-MCI has, indeed, allowed a patient's improved constitution to be demonstrated; this has also been assessed in rarer treatment scenarios, such as in younger, high-risk patients undergoing immunotherapy approaches, i.e. allo-SCT. Here, although patients grew older and renal function declined over time, the median R-MCI improved from 4 before allo-SCT to 3 after allo- SCT (Table 1).23,45
5. In frail patients, being able to see if there is any dete- rioration in the R-MCI makes it easier to adapt or inter- rupt treatment. This underscores its clinical helpfulness. For example, since the QoL in a light chain (AL)-amyloi- dosis patient did not improve, even though hematologic response was achieved, the use of the R-MCI facilitated supportive treatment rather than continuation of exten- sive and expensive care.10,46
6. Inclusion of the R-MCI in future study protocols at our center, and in discussion with both German MM study groups (DSMM and GMMG) is under way.
Conclusions
Although the IMWG-frailty score is a “reference” comorbidity index,18 others are more straightforward to use. The inclusion of “Lung function” in the R-MCI had been repeatedly requested by reviewers as a more objec- tive measure than via the GOLD criteria, smoking status or dyspnea upon exertion, and is included in the diagnos- tic workup at our center (i.e. before intensive treatment, such as SCT).11,12,21,44-47 If unavailable, smoking status, its mandatory cessation before SCT/intensive treatment, no advanced GOLD criteria, and no dyspnea upon exertion have been used as substitutes in prior analyses.24-26
 Figure 1. Environmental and genetic factors that influence key cellular processes and pathways defined as hallmarks of aging. Many pathways contribute to the creation of a chronic inflammatory stage and to aging. These in turn increase the risk of chronic disease of aging together with disease-specific risk factors, i.e. in multiple myeloma (MM): polyneuropathy, osteoporosis/osteopenia, bone fractures, anemia. All eventually induce frailty, disability, mortality and geriatric syndromes, and potentially decrease patients' quality of life (adapted and with permission of J. Campisi et al.)50
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