Abstract
Objectives
This study aimed to evaluate the relationship between the degree of bone marrow involvement, hematological parameters, and 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography/computed tomography (PET/CT) data in patients diagnosed with multiple myeloma.
Methods
A total of 71 patients [19 females, 52 males, mean age 67 (36-83) years] who were diagnosed with multiple myeloma between 2014 and 2021, had not received any treatment yet, and underwent 18F-FDG-PET/CT for staging were included in the study.
Results
No significant correlation was observed between bone marrow standardized uptake value (SUV)max and plasma cell infiltration (p=0.07). However, we found that patients with visually increased bone marrow counts also had higher plasma cell infiltration rates (p=0.037). No significant correlation was found between plasma cell infiltration rates and bone marrow SUVmax and systemic inflammatory index (SII) (p=0.187 and p=0.446, respectively). However, there was a significant correlation between the SUVmax of lytic lesions showing increased 18F-FDG uptake in bone and SII (p=0.025, r=0.330).
Conclusion
We believe that 18F-FDG PET/CT may be an advantage over bone marrow biopsy in the diagnosis and evaluation of multiple myeloma recurrence and may prevent repeated bone marrow biopsies.
Introduction
Multiple myeloma constitutes 1% of all cancers and ~13% of hematological malignancies (1, 2). In addition, it has been the focus of studies because it is the 2nd most common cancer type after non-Hodgkin lymphoma in hematological malignancies, and its incidence has increased by 126% from 1991 to 2016 (1, 3). Multiple myeloma is a malignancy characterized by the uncontrolled proliferation of clonal plasma cells in bone marrow and by the secretion of monoclonal immunoglobulin protein (M protein) (2, 3, 4).
The National Comprehensive Cancer Network recommendations for staging patients with multiple myeloma at diagnosis are positron emission tomography/computed tomography (PET/CT) or whole-body low-dose CT (5).
As in many other cancers, 18F-fluorodeoxyglucose (18F-FDG)-PET/CT is an imaging system used in staging and treatment diagnosis evaluation of hematological malignancies (6, 7). 18F-FDG-PET/CT is an effective method for detecting skeletal and extramedullary lesions in multiple myeloma patients (8).
We aimed to investigate the potential distribution of bone marrow plasma cell infiltration rates, PET/CT data, and hematological parameters in multiple myeloma. Thus, we aimed to determine whether 18F-FDG-PET/CT can be used instead of repeated invasive bone marrow biopsy when investigating the diagnosis and recurrence of patients.
Materials and Methods
A total of 71 patients [19 females, 52 males, mean age 67 (36-83) years] diagnosed with multiple myeloma between 2014 and 2021, who had not received any treatment yet, and who underwent 18F-FDG-PET/CT for staging purposes were included in the study. Our study was retrospective, and informed consent was obtained from all patients.
No patient diagnosed outside Sivas Cumhuriyet University and/or who underwent 18F-FDG PET/CT at an external center were included in the study. Patients who received treatment after diagnosis or for other malignancies were also excluded.
Bone marrow aspiration results and creatinine, albumin, calcium, neutrophil, lymphocyte, beta-2 microglobulin, and platelet values were recorded from blood samples obtained within 2 weeks after the diagnosis of 18F-FDG-PET/CT. The systemic inflammatory index (SII) of the patients was calculated using the neutrophil x lymphocyte/platelet formula.
Standardized uptake value maxima (SUVmax) values, which were calculated with 18F-FDG PET/CT software in the Department of Nuclear Medicine, and the presence/absence of metastases detected by 18F-FDG PET/CT were recorded.
In PET/CT image analysis, when bone lesions were evaluated, uptake greater than background bone marrow activity was considered positive. A bone marrow SUVmax > hepatic SUVmax was considered positive for diffuse bone marrow infiltration.
Approval for this study was obtained from the Sivas Cumhuriyet University Non-Invasive Clinical Research Ethics Committee (decision no: 2022-01/21, date: 13.01.2022).
18F-FDG PET/CT Imaging Protocol
Blood sugar levels of patients who remained open for a minimum of 4-6 hours were measured before the 18F-FDG injection. Injection was allowed for patients whose blood sugar was below <200 mg/dL. 0.1 mCi 18F-FDG per kilogram was recorded in the patients, and after being stored for 45-60 minutes, Three-dimensional PET/CT images were taken from the skull to the tip of the foot. A General Electric Discovery PET/CT 600 device was used for imaging. CT imaging, attenuation correction, and anatomical correlation were performed with a spiral 16-slice scanner at 120 kV and 172 mAs. During imaging, images were taken for approximately 2-3 min in each bed position. Axial, coronal, and sagittal fusion images were created using the Iterative reconstruction method. SUVmax were calculated from PET images. In the PET images, the region of interest (ROI) was placed within the primary tumor, avoiding the peripheral area. The following formula was used to calculate the SUVmax: [Activity in ROI (mCi/mL)×Body Weight (grams)]÷Injected Dose (mCi)
Statistical Analysis
The data obtained from our study were evaluated using SPSS 23.0 software. The normality of the data was analyzed using the Kolmogorov-Smirnov test. Because the parametric conditions of the data were not met, the Mann-Whitney U test was used for two independent groups and the Kruskal-Wallis test for more than two independent groups. When analysis of variance was used for comparisons with more than two groups, Tukey’s T2 test was used to determine which group was different from the others when the homogeneity assumption was met, and Tamhane’s T2 test was used when the homogeneity assumption was not met. The chi-square test was used to evaluate the data obtained by counting. The p-values ≤0.05 were accepted statistically significant.
Results
The mean bone marrow SUVmax was 2.3 (range: 1-7.6). Forty-one (58%) patients had bone marrow enhancement visualized on PET/CT, whereas 30 (42%) did not. The correlation between the rates of plasma cell infiltration and the rates of visualized bone marrow enhancement was statistically significant (p=0.037). There was no significant correlation between bone marrow plasma cell infiltration rate and bone marrow SUVmax value (p=0.072) (Table 1). There was no significant correlation between plasma cell infiltration rates and the presence of lytic lesions with increased 18F-FDG uptake >5 mm on PET/CT (p=0.05). In addition, no significant correlation was found between plasma cell infiltration rate and SUVmax of the lytic lesion (p=0.07).
No significant correlation was found between plasma cell infiltration rate and SII (p=0.187). No significant correlation was found between bone marrow SUVmax and SII (p=0.446) (Table 1). There was a significant correlation between bone lytic lesion SUVmax and SII (p=0.025, r=0.330). There was a significant correlation between bone marrow SUVmax and creatinine elevation (p=0.032) (Table 1). There was also a significant correlation between the presence of lytic lesions in bone and creatinine elevation (p=0.026). However, there was no significant correlation between the SUVmax of lytic lesions in bone and creatinine elevation (p=0.156). However, no significant correlation was found between bone marrow SUVmax and parameters such as platelet, hemoglobin, calcium, beta- 2 microglobulin, and albumin (p=0.977, p=0.806, p=0.505, p=0.216, p=0.423, respectively) (Table 1).
Discussion
No significant correlation was found between plasma cell infiltration rate. The presence of bone marrow involvement and the extent of extramedullary tissue involvement are important factors affecting the prognosis and clinical management of patients with multiple myeloma.
In their study, Sager et al. (9) found a significant correlation between bone marrow biopsy cellularity, plasma cell ratio, and bone marrow SUVmax. In conclusion, the correlation between bone marrow SUVmax and plasma cell ratio suggested that PET/CT could prevent repeated bone marrow biopsies during follow-up.
Ak and Gulbas (10) showed that increased 18F-FDG uptake in the bone marrow of patients with multiple myeloma was associated with the percentage of plasma cell infiltration in the bone marrow. Therefore, the authors stated that the 18F-FDG-PET/CT study may be a valuable tool for estimating the levels of myeloma cells in bone marrow, and it is an imaging method that can be used in response to treatment and follow-up of patients.
However, our study found that plasma cell infiltration rates were also high in patients with visually increased bone marrow. Still, we did not find any significant correlation between bone marrow SUVmax and plasma cell infiltration rates. This may be due to the limited number of patients or the individual differences in the fields on which we based the bone marrow SUVmax levels.
Cengiz et al. (11) in their study, no correlation was found between the 18F-FDG uptake rate of bone marrow and calcium, albumin, and beta-2 microglobulin levels, which is consistent with our study.
However, a significant correlation was observed between the 18F-FDG uptake rate in bone marrow and creatinine elevation. In addition, the presence or absence of lytic lesions in bone was significantly correlated with creatinine elevation. This is related to disease aggressiveness.
According to Kim et al., (12), regarding hematological parameters, a high neutrophil-to-lymphocyte ratio, low platelet count, and high c-reactive protein were found to be independently negatively associated with overall survival. In a study by Shi et al., (13) high neutrophil-to-lymphocyte ratio and low platelet-to-lymphocyte ratio were compatible with poor prognostic clinical results and suggested their utility as prognostic biomarkers.
Recently, the SII based on peripheral platelet, neutrophil, and lymphocyte counts has been shown to be a promising prognostic indicator in various diseases.
In our study, there was a significant correlation between SII and the SUVmax value of the lytic lesion in the bone (p=0.025, r=0.330). Many studies have reported that high tumor lesion SUVmax and SII values increase tumor aggressiveness and poor prognosis (14, 15, 16). For this reason, we believe that we found a correlation between bone lesion SUVmax and SII values in our study. We believe that patients with a high lesion SUVmax value will also have a high SII and a worse prognosis. Therefore, it should be kept in mind that anti-inflammatory therapies may be added to such patients during follow-up. The most important limitation of our study is that we could not reach the targeted number of patients and could not evaluate the prognosis of the patients.
Conclusion
No significant correlation was observed between bone and bone marrow uptake and bone marrow plasma cell infiltration rate on 18F-FDG PET/CT. However, our study found that patients with visually increased bone marrow uptake also had high plasma cell infiltration rates. In conclusion, we believe that 18F-FDG PET/CT may be an advantage of bone marrow biopsy in the diagnosis and evaluation of the recurrence of multiple myeloma and may prevent repeated bone marrow biopsies.
In addition, our study showed a significant correlation between the SUVmax of lytic lesions in bone and SII (p=0.025, r=0.330). Therefore, we believe that the prognosis will worsen as the SUVmax of lytic lesion increases.
In addition, increased serum creatinine levels were associated with bone marrow SUVmax. We believe this is also related to the aggressiveness of the disease and poor prognosis.
We found 4 studies investigating the relationship between 18F-FDG-PET/CT parameters and bone marrow plasma cell infiltration rate in multiple myeloma. Although the number of patients included in these studies was insufficient, we believe that further studies would be useful to provide an advantage to bone marrow biopsy, an invasive method for the diagnosis and follow-up of multiple myeloma. In this regard, we believe that our study results are valuable.
