Multiple myeloma occurs primarily in elderly patients. Considering the high prevalence of comorbidities, comorbidity is an important issue for the management of myeloma. However, the impact of comorbidity on clinical outcomes has not been fully investigated. We retrospectively analyzed patients with newly diagnosed myeloma. Comorbidities were assessed based on the Charlson comorbidity index (CCI) and the Freiburg comorbidity index (FCI). The CCI is a summary measure of 19 comorbid conditions. FCI is determined by performance status, renal impairment, and lung disease. This study included 127 patients with a median age of 71 years. Approximately half of the patients had additional disorders at the time of diagnosis, and diabetes mellitus was the most frequent diagnosis (18.9%). The most significant factors for prognosis among patient-related conditions were a history of solid cancer and performance status (ECOG ≥ 2). The FCI score was divided into 3 groups (0, 1, and 2-3), and the CCI score was divided into 2 groups (2-3 and ≥4). FCI was a strong prognostic tool for OS (
Multiple myeloma (MM) is a hematologic malignancy of plasma cells that results in bone destruction, marrow failure, and renal impairment. The median age at the time of diagnosis is 70 years, with 36% of patients younger than 65 years, 27% aged 65 to 74 years, and 37% older than 75 years [
Risk stratification of myeloma using the international staging system (ISS) and host factors such as age, performance status, and comorbidities are thought to be important for determining prognosis and choosing treatment options [
Kleber et al. developed the Freiburg comorbidity index (FCI) to assess patient-related conditions as a risk factor for MM. The FCI is composed of three comorbidity factors: renal impairment, moderate to severe lung disease, and performance status. Interestingly, the FCI showed strong clinical relevance for overall survival (OS) and progression-free survival (PFS). Moreover, compared with other comorbidity indices, such as the Charlson comorbidity index (CCI), hematopoietic cell transplantation-specific comorbidity index (HCT-CI), Kaplan-Feinstein (KF), and Satariano index (SI), FCI was better able to stratify risk in patients with MM [
Although CCI is a widely used tool for assessing comorbidity in malignancy, this comorbidity index is complicated and difficult to apply. Moreover, there is no proven cut-off value that divides patients into low- or high-risk groups. As a result, several studies have determined their own cut-off values [
Because of the increased incidence of multiple myeloma with aging and the fact that elderly patients have more comorbidity than younger patients, in the present study, we assessed comorbidities at diagnosis, the impact of host factors on OS, and compared CCI and FCI as prognostic factors in newly diagnosed elderly patients with MM.
This study was a retrospective, single-center case series. OS was calculated as the time from diagnosis to death from any cause. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0. This study was reviewed and approved by the Institutional Review Board.
A total of 127 consecutive patients aged 65 years and older who were newly diagnosed with symptomatic MM at the Samsung Medical Center, Seoul, South Korea, between January 1, 1999, and June 30, 2011, met the inclusion criteria for this study. We excluded patients with amyloidosis, those who were suitable for autologous stem cell transplantation (ASCT), and those who were lost to follow-up within 6 months from the time of diagnosis due to any cause except death. The last follow-up date was March 31, 2013.
The CCI (Table
Definitions of the Charlson and Freiburg comorbidity indices.
Weight | Condition | Definition |
---|---|---|
|
||
1 | Myocardial infarct | Hospitalization and electrocardiographic and/or enzyme change |
Congestive heart failure | Exertional or paroxysmal nocturnal dyspnea and responded symptomatically (or on physical examination) to digitalis, diuretics, or afterload reducing agents | |
Peripheral vascular disease | Intermittent claudication or prior bypass for arterial insufficiency; gangrene or acute arterial insufficiency; untreated thoracic or abdominal aneurysm (≥6 cm) | |
Cerebrovascular disease | Cerebrovascular accident with minor or no residual and transient ischemic attacks | |
Dementia | Chronic cognitive deficit | |
Chronic pulmonary disease |
| |
Connective tissue disease | SLE, PM, MCTD, polymyalgia rheumatic, and moderate to severe RA | |
Ulcer disease | Required treatment for ulcer disease, including bleeding from ulcers | |
Mild liver disease | Cirrhosis without portal hypertension or chronic hepatitis | |
Diabetes |
| |
|
||
2 | Hemiplegia | Dense hemiplegia or paraplegia, as a result of either a cerebrovascular accident or other conditions |
Moderate or severe renal disease |
| |
Diabetes with end organ damage |
| |
Any tumor | Solid tumors without documented metastases, but initially treated in the last 5 years | |
Leukemia | AML, CML, ALL, CLL, and PV | |
Lymphoma | HD, lymphosarcoma, WM, myeloma, and other lymphomas | |
|
||
3 | Moderate or severe liver disease |
|
|
||
6 | Metastatic solid tumor | Metastatic solid tumors |
AIDS | Define or probable AIDS (i.e., AIDS related complex) | |
|
||
|
||
1 | Renal impairment | eGFRMDRD ≤ 30 mL/min/1.73 m2 |
Performance status | Karnofsky performance status (KPS) score ≤ 70 | |
Moderate or severe lung disease | Same as CCI |
Abbreviations: SLE, systemic lupus erythematous; PM, polymyositis; MCTD, mixed connective tissue disease; RA, rheumatoid arthritis; AML, acute myelogenous leukemia; CML, chronic myelogenous leukemia; ALL, acute lymphocytic leukemia; CLL, acute lymphocytic leukemia; PV, polycythemia vera; HD, Hodgkin disease; WM, Waldenstrom’s macroglobulinemia; AIDS, acquired immune deficiency syndrome; eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease; CCI, Charlson comorbidity index.
In addition, according to the original study, each decade of age over 40 would add 1 point to the risk value (i.e., 50 years = +1 point), and the age point would be added to the score of the comorbidity index. In this study, we used the method described by Kleber et al., which adds the age point to the CCI score [
Renal impairment is defined as estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m2, based on the modification of diet in renal disease (MDRD) study equation [
Numerical variables are summarized by median and range and categorical variables are described by count and relative frequency (%) of subjects in each category. Comparison of the distribution of categorical variables in the different groups was performed with either Fisher’s exact test or the
These analyses were performed using PASW statistics 18.0.0 (WinWrap, IBM, New York, USA). Null hypotheses of no difference were rejected if
During the study period, a total of 159 patients aged 65 years or older were newly diagnosed with symptomatic MM. Among them, 22 patients were excluded because of a combined diagnosis of amyloidosis, early follow-up loss, or ASCT. Therefore, data from 127 patients were included in the analysis.
Table
Baseline characteristics (
Characteristics |
|
Median (range) |
---|---|---|
Age, years | 71 (65–92) | |
65–74 | 93 (73.2%) | |
|
34 (26.8%) | |
Sex | ||
Male | 62 (48.8%) | |
Female | 65 (51.2%) | |
ECOG | ||
0-1 | 74 (58.3%) | |
|
52 (40.9%) | |
Unknown | 1 (0.8%) | |
Durie-Salmon stage | ||
1 | 10 (7.9%) | |
2 | 28 (22.0%) | |
3 | 89 (70.1%) | |
International staging system | ||
1 | 23 (18.1%) | |
2 | 51 (40.2%) | |
3 | 47 (37.0%) | |
Unknown | 6 (4.7%) | |
Lytic bone lesion | ||
Yes | 112 (88.2%) | |
No | 14 (11.0%) | |
Hemoglobin (g/dL) | 9.66 (5.20–16.30) | |
|
75 (59.1%) | |
|
52 (40.9%) | |
Platelets (×109/L) | 195 (44–484) | |
|
11 (8.7%) | |
|
117 (91.3%) | |
Plasma cells in bone marrow (%) | 43.88 (1.10–100) | |
|
58 (45.7%) | |
|
65 (51.2%) | |
Serum calcium (mg/dL) | 9.35 (7.00–15.70) | |
|
11 (8.7%) | |
|
115 (90.6%) | |
Serum albumin (mg/dL) | 3.28 (1.70–4.80) | |
|
85 (66.9%) | |
|
42 (33.1%) | |
eGFR (mL/min/1.73 m2) | 66.60 (5.90–170.5) | |
|
112 (88.2%) | |
|
15 (11.8%) | |
Serum LD | ||
|
27 (21.3%) | |
|
74 (58.3%) | |
Initial chemotherapy regimen | ||
Conventional (CP, MP, and others) | 92 (78.0%) | |
Novel agents (imid, bortezomib-based) | 26 (22.0%) | |
Treatment | ||
Chemotherapy | 118 (92.9%) | |
No chemotherapy | 9 (7.1%) |
ECOG, eastern cooperative oncology group; eGFR, estimated glomerular filtration rate; LD, lactate dehydrogenase; UNL, upper normal limit; CP, cyclophosphamide and prednisolone; MP, melphalan and prednisolone.
The prevalence of comorbidity at the time of diagnosis was 48.8% (Table
Prevalence of comorbidities according to the Charlson and Freiburg comorbidity indices and patient distribution according to comorbidity indices.
Prevalence of comorbidities according to the Charlson comorbidity index.
Comorbidity | Yes | No |
---|---|---|
Myocardial infarct | 7 (5.5%) | 120 (94.5%) |
Congestive heart failure | 7 (5.5%) | 120 (94.5%) |
Peripheral vascular disease | 0 (0%) | 127 (100%) |
Cerebrovascular disease | 6 (4.7%) | 121 (95.3%) |
Dementia | 0 (0%) | 127 (100%) |
Chronic lung disease | 14 (11.0%) | 113 (89.0%) |
Connective tissue disease | 2 (1.6%) | 125 (98.4%) |
Ulcer disease | 8 (6.3%) | 119 (93.7%) |
Mild liver disease | 2 (1.6%) | 125 (98.4%) |
DM | 24 (18.9%) | 103 (81.1%) |
Hemiplegia | 6 (4.7%) | 121 (95.3%) |
Moderate to severe renal disease | 1 (0.8%) | 126 (99.2%) |
DM with end organ damage | 0 (0%) | 127 (100%) |
Any tumor | 8 (6.3%) | 119 (93.7%) |
Leukemia | 0 (0%) | 127 (100%) |
Lymphoma | 0 (0%) | 127 (100%) |
Moderate to severe liver disease | 2 (1.6%) | 125 (98.4%) |
Metastatic solid tumor | 2 (1.6%) | 125 (98.4%) |
AIDS | 0 (0%) | 127 (100%) |
DM, diabetes mellitus; AIDS, acquired immune deficiency syndrome.
Prevalence of comorbidities according to the Freiburg comorbidity index.
Component | Yes | No |
---|---|---|
Renal impairment |
15 (11.8%) | 112 (88.2%) |
Performance status (KPS ≤ 70) | 52 (40.9%) | 74 (58.3%) |
Moderate or severe lung disease | 14 (11.0%) | 113 (89.0%) |
eGFR, estimated glomerular filtration rate; KPS, Karnofsky performance status.
Patient distribution according to comorbidity indices.
(I) CCI total |
|
0 | 65 (51.2%) |
1 | 37 (29.1%) |
2 | 12 (9.4%) |
3 | 5 (3.9%) |
4 | 6 (4.7%) |
6 | 1 (0.8%) |
8 | 1 (0.8%) |
(II) CCI total |
|
2 | 25 (19.7%) |
3 | 49 (38.6%) |
4 | 31 (24.4%) |
5 | 9 (7.1%) |
6 | 5 (3.9%) |
7 | 6 (4.7%) |
9 | 1 (0.8%) |
13 | 1 (0.8%) |
(III) CCI score group (with age points) | |
Low (2-3) | 53 (41.7%) |
High (≥4) | 74 (58.3%) |
(IV) FCI | |
0 | 59 (46.5%) |
1 | 54 (425%) |
2 | 12 (9.4%) |
3 | 1 (0.8%) |
Unknown | 1 (0.8%) |
CCI, Charlson comorbidity index; FCI, Freiburg comorbidity index.
We analyzed the impact of host factors, such as age, sex, performance status, and each of the comorbidities on OS (Table
Univariate and multivariate Cox’s regression analysis for overall survival.
Univariate analysis | Multivariate analysis | |||||
---|---|---|---|---|---|---|
|
HR | 95% CI |
|
HR | 95% CI | |
ECOG | 0.002 | 1.951 | 1.287–2.958 | 0.009 | 1.890 | 1.176–3.038 |
0-1 | ||||||
≥2 | ||||||
Chronic lung disease | 0.028 | 1.941 | 1.073–3.510 | 0.300 | 1.425 | 0.730–2.778 |
Yes | ||||||
No | ||||||
eGFR (mL/min/1.73 m2) | 0.012 | 2.139 | 1.183–3.869 | 0.228 | 1.515 | 0.771–2.976 |
|
||||||
|
||||||
Any tumor | 0.001 | 3.513 | 1.678–7.356 | 0.003 | 3.717 | 1.617–8.554 |
Yes | ||||||
No | ||||||
Metastatic solid tumor | <0.001 | 44.034 | 8.449–229.485 | <0.001 | 85.847 | 14.628–503.822 |
Yes | ||||||
No | ||||||
Cerebrovascular disease | 0.016 | 3.064 | 1.228–7.641 | 0.210 | 1.855 | 0.706–4.887 |
Yes | ||||||
No | ||||||
International staging system | 0.024 | 0.250 | ||||
1 | ||||||
2 | ||||||
3 | ||||||
Age, years | 0.339 | 1.242 | 0.796–1.938 | |||
65–74 | ||||||
|
||||||
Sex | 0.692 | 0.920 | 0.610–1.388 | |||
Male | ||||||
Female | ||||||
Durie-Salmon stage | 0.242 | |||||
1 | ||||||
2 | ||||||
3 | ||||||
Myocardial infarct | 0.146 | 1.783 | 0.818–3.884 | |||
Yes | ||||||
No | ||||||
Congestive heart failure | 0.581 | 1.329 | 0.484–3.644 | |||
Yes | ||||||
No | ||||||
Connective tissue disease | 0.302 | 0.047 | 0.000–15.543 | |||
Yes | ||||||
No | ||||||
Ulcer disease | 0.196 | 0.571 | 0.244–1.334 | |||
Yes | ||||||
No | ||||||
Mild liver disease | 0.262 | 2.246 | 0.545–9.249 | |||
Yes | ||||||
No | ||||||
DM | 0.256 | 0.718 | 0.405–1.272 | |||
Yes | ||||||
No | ||||||
Hemiplegia | 0.081 | 0.353 | 0.110–1.135 | |||
Yes | ||||||
No | ||||||
Moderate to severe renal disease | 1.000 | 1.000 | 0.000–4.271 |
|||
Yes | ||||||
No | ||||||
Moderate-severe liver disease | 0.302 | 2.100 | 0.514–8.583 | |||
Yes | ||||||
No | ||||||
Initial chemotherapy regimen | 0.844 | 1.058 | 0.603–1.858 | |||
Conventional agents | ||||||
Novel agent | ||||||
CCI | 0.061 | 0.677 | 0.450–1.018 | |||
2-3 | ||||||
|
||||||
FCI | <0.001 | |||||
0 | ||||||
1 | ||||||
2-3 |
HR, hazard ratio; CI, confidence interval; ECOG, eastern cooperative oncology group; eGFR, estimated glomerular filtration rate; DM, diabetes mellitus; CCI, Charlson comorbidity index; FCI, Freiburg comorbidity index.
Figures
Kaplan-Meier survival curves of comorbidity index score groups. OS according to FCI.
Kaplan-Meier survival curves of comorbidity index score groups. OS according to FCI in patients aged 65–74 years.
Kaplan-Meier survival curves of comorbidity index score groups. OS according to FCI in patients aged ≥75 years.
Kaplan-Meier survival curves of comorbidity index score groups. OS according to CCI.
We defined serious adverse events as grade ≥4 for hematologic adverse events and grade ≥3 for nonhematologic adverse events, according to NCI-CTC version 4.0. The most frequent serious adverse event was infection (
Serious adverse events (AEs).
|
||
---|---|---|
Grade 0–3 | Grade 4-5 | |
Hematologic AE | ||
Anemia | 103 (87.3%) | 15 (12.7%) |
Neutropenia | 103 (87.3%) | 15 (12.7%) |
Thrombocytopenia | 114 (92.2%) | 4 (7.8%) |
Febrile neutropenia | 113 (90.8%) | 5 (9.2%) |
|
||
Grade 0–2 | Grade 3–5 | |
|
||
Nonhematologic AE | ||
Infection | 83 (70.0%) | 35 (30.0%) |
Diarrhea/constipation | 105 (89.0%) | 13 (11.0%) |
Fatigue | 117 (90.7%) | 11 (9.3%) |
Sensory neuropathy | 108 (91.5%) | 10 (8.5%) |
Nausea/vomiting | 111 (94.1%) | 7 (5.9%) |
Azotemia | 112 (94.9%) | 6 (5.1%) |
|
||
Grade ≥4 hematologic AE | 27 (22.9%) | |
Grade ≥3 nonhematologic AE | 59 (50.0%) | |
Grade 5 AE | 8 (6.8%) |
This study assessed comorbidities at diagnosis of MM, the impact of host factors on overall survival, and compared CCI and FCI as prognostic factors in newly diagnosed elderly patients.
Univariate analysis revealed that performance status, ISS, and several comorbid conditions such as chronic lung disease, azotemia (eGFR < 30 mL/min/1.73 m2), presence of any tumor, metastatic solid tumor, and cerebrovascular disease were significant factors. However, azotemia as defined by CCI (serum creatinine ≥ 3 mg/mL) was not a prognostic factor. In multivariate analysis, azotemia, as defined by impaired eGFR or chronic lung disease, was not shown to be a significant risk factor in our study. In contrast, a history of cancer, regardless of whether metastasis occurred, was the strongest prognostic factor for elderly patients with myeloma. Unfortunately, use of novel agents over conventional drugs did not significantly improve OS, although this might reflect the relatively short period of use of novel agents.
Although two components of FCI-renal impairment and moderate or severe lung disease failed to demonstrate significance in multivariate analysis, when we compared both comorbidity indices and overall survival, the FCI showed a greater ability to separate OS among the three score groups (
FCI provides a clear definition of each component and all three components were statistically significant, at least in univariate analysis. In contrast, CCI is more subjective and only 4 among 19 conditions were significant. Most importantly, at the present time, CCI does not have any standard cut-off value. Various studies have divided CCI scores into groups of 0, 1-2, and ≥3; 0, 1, and ≥2; or 0 and ≥1. Some studies included an age point, but others did not [
Moreover, FCI is also very simple to apply. FCI consists of performance status, moderate or severe lung disease, and azotemia, and each of these factors is worth 1 point. The FCI score is, therefore, a simple summation of these three factors. In contrast, CCI consists of 19 comorbid conditions, and, within the same disease, scores are weighted based on severity ranging from 1 to 6 points. In addition, an age point is calculated and added to the CCI score. Comorbidity definitions frequently use a symptomatic grade.
In this study, all 118 patients who were treated with chemotherapy received a full dose of chemotherapeutic agents as scheduled. Interestingly, the profile for serious adverse events showed that treatment was relatively safe and adverse events were easily controllable. In fact, since the approval of various novel agents, clinical outcomes such as survival and toxicity profiles have improved in transplant-ineligible elderly patients with multiple myeloma [
There are some limitations in this study. First, the follow-up duration was short and the sample size was small. Second, this is a retrospective single center study. Third, there were no patients with peripheral vascular disease, dementia, DM with end organ damage, or AIDS. Despite these limitations, this study successfully applied the FCI and the CCI to newly diagnosed elderly multiple myeloma patients and revealed the superiority of FCI to CCI in predicting OS.
In this study, approximately 50% of elderly patients with newly diagnosed multiple myeloma had at least one comorbid disease at the time of diagnosis. Among host factors tested, performance status and a history of malignancy were the most important prognostic factors. The Freiburg comorbidity index is very simple to use and predicts overall survival better than the Charlson comorbidity index.
The authors declare that there is no conflict of interests regarding the publication of this paper.