A concise revised Myeloma Comorbidity Index as a valid prognostic instrument in a large cohort of 801 multiple myeloma patients

Abstract

With growing numbers of elderly multiple myeloma patients, reliable tools to assess their vulnerability are required. The objective of the analysis herein was to develop and validate an easy to use myeloma risk score (revised Myeloma Comorbidity Index) that allows for risk prediction of overall survival and progression-free survival differences in a large patient cohort. We conducted a comprehensive comorbidity, frailty and disability evaluation in 801 consecutive myeloma patients, including comorbidity risks obtained at diagnosis. The cohort was examined within a training and validation set. Multivariate analysis determined renal, lung and Karnofsky Performance Status impairment, frailty and age as significant risks for overall survival. These were combined in a weighted revised Myeloma Comorbidity Index, allowing for the identification of fit (revised Myeloma Comorbidity Index ≤3 [n=247, 30.8%]), intermediate-fit (revised Myeloma Comorbidity Index 4-6 [n=446, 55.7%]) and frail patients (revised Myeloma Comorbidity Index >6 [n=108, 13.5%]): these subgroups, confirmed via validation analysis, showed median overall survival rates of 10.1, 4.4 and 1.2 years, respectively. The revised Myeloma Comorbidity Index was compared to other commonly used comorbidity indices (Charlson Comorbidity Index, Hematopoietic Cell Transplantation-Specific Comorbidity Index, Kaplan-Feinstein Index): if each were divided in risk groups based on 25% and 75% quartiles, highest hazard ratios, best prediction and Brier scores were achieved with the revised Myeloma Comorbidity Index. The advantages of the revised Myeloma Comorbidity Index include its accurate assessment of patients' physical conditions and simple clinical applicability. We propose the revised Myeloma Comorbidity Index to be tested with the "reference" International Myeloma Working Group frailty score in multicenter analyses and future clinical trials. The study was registered at the German Clinical Trials Register (DRKS-00003868).

Figure 1.

Frequency of entire (blue columns) and moderate-severe (yellow columns) organ impairment. Frequency of relevant comorbidities and impairment of general condition in all MM patients. Proportion of patients with any degree of impairment/grade of severity (blue bars) vs. proportion of patients with moderate to severe impairment/grade of severity (red bars). For cardiac function, hepatic function, GI disease, infection, thrombosis and renal function the CTCAE grading system was used, with CTCAE 1–4 (blue bars) vs. CTCAE ≥2 (red bars). KPS and lung function was graded as described.^–,,, Frailty was graded according to the definition of Rodriguez-Mañas L et al. and Fried LP et al. Disability was graded as described.^, Table 1 shows the definition and grading of all assessed comorbidities. GI: gastrointestinal; KPS: Karnofsky Performance Status; pts: patients.

Figure 2.

OS (A–D) and PFS (E–H) using the R-MCI (left) and I-MCI (right) in training and validation analyses. Overall survival (OS: A–D) and progression-free survival (PFS: E–H) curves using the revised MCI (R-MCI) and initial MCI (I-MCI) in the training and validation sets. Fit patients, with the use of the R-MCI, were defined with 0–3, intermediate with 4–6 and frail patients with 7–9 R-MCI points; with the use of the I-MCI with 0, 1 and 2–3 points, respectively. The survival curves of the R-MCI were stratified based on 25% and 75% quantiles leading to a stratification of fit patients with ≤3 R-MCI points, intermediate-fit patients with 4–6 R-MCI points and frail patients with >6 R-MCI points. The numbers of patients at risk in the respective groups are given below each Kaplan-Meier plot. PFS with the use of the R-MCI generated better group distinction both in the training set (E) and validation set (G) than with the use of the I-MCI (F and H). In line, OS was better distinguishable in 3 risk groups via the R-MCI in the training set (A) and validation set (C) vs. with the use of the I-MCI (B and D). R-MCI: revised Myeloma Comorbidity Index; I-MCI: initial Myeloma Comorbidity Index.

Figure 3.

OS with the use of the R-MCI with different treatment intensity and age groups. OS with the use of the R-MCI in different treatment (A–D) and age cohorts (E,F), demonstrated excellent risk allocations of fit, intermediate and unfit patients with vs. without stem cell transplantation (A,B), with vs. without novel agent treatment (C,D) and <65 vs. >65 year old patients (E,F). Tx: transplantation; NA: novel agents; w: with; w/o: without.

Figure 4.

Scoring factors and maximum points of the R-MCI as compared to the IMWG frailty index, CCI, HCT-CI, KFI and R-ISS. Single factors of respective internationally used comorbidity scores, namely the IMWG frailty index, HCT-CI, KFI and R-ISS and R-MCI are displayed with their respective comorbidities therein. The number of risk factors and maximum score that can be achieved is also depicted. Moreover, respective overlapping risk factors with the R-MCI are shown. Impaired general condition is differently assessed with various scores, e.g., with the R-MCI via Karnofsky Performance Status (KPS) and frailty; with the IMWG frailty index via ADL and IADL and with the KFI via assessment of any locomotor impairment. IMWG: International Myeloma Working Group; CCI: Charlson Comorbidity Index; (I)ADL: (Instrumental) Activity of Daily Living; AIDS: Acquired Immune Deficiency Syndrome. HCT-CI: Hematopoietic cell transplantation-specific Comorbidity Index; R-MCI: revised Myeloma Comorbidity Index; KFI: Kaplan-Feinstein Index; ISS: International Staging System; R-ISS: revised ISS; LDH: lactate dehydrogenase.